Bioequivalence and Bioavailability Forum

Main page Policy/Terms of Use Abbreviations Latest Posts

 Log-in |  Register |  Search

Back to the forum  Query: 2017-09-23 13:07 CEST (UTC+2h)
 
nobody
Senior

2016-01-15 16:49

Posting: # 15829
Views: 16,397
 

 Death in phase I cannabinoid? [Off Topic]

Hy again!

Any details available from serious sources on this:

https://news.yahoo.com/one-person-brain-dead-five-hospitalised-french-drug-104040442.html

Many thanx in advance!

Kindest regards, nobody
Helmut
Hero
Homepage
Vienna, Austria,
2016-01-15 17:25

@ nobody
Posting: # 15830
Views: 15,023
 

 Death in phase I cannabinoid?

Hi nobody,

» Any details available from serious sources on this:
» https://news.yahoo.com/one-person-brain-dead-five-hospitalised-french-drug-104040442.html

Nope. That’s bizarre. Oral cannabinoids could never act as “painkillers” (fast acting) due to their low absorption, and extensive pre-systemic + first-pass metabolism. A few oral formulations were developed in the indication neuropathic pain but AFAIK none of them made it to approval so far. Would be interesting which cannabinoid was tested. Can’t imagine such shit [sic] happening with Δ9-THC (dronabinol) or cannabdiol.

Wait a minute.
http://www.independent.co.uk/news/world/europe/france-clinical-trial-one-person-brain-dead-and-five-more-in-hospital-after-drug-testing-a6813791.html
“Marisol Touraine, the French health minister, later said that the pill did not contain cannabis or its derivatives but acted on the body’s endocannabinoid system.”

Hhm.

The official press-release is not helpful. If you know French:
http://www.ouest-france.fr/bretagne/rennes-35000/essai-therapeutique-rennes-un-patient-en-etat-de-mort-clinique-3972041

[image]All the best,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
nobody
Senior

2016-01-15 17:45
(edited by nobody on 2016-01-15 17:57)

@ Helmut
Posting: # 15831
Views: 14,884
 

 Death in phase I cannabinoid?

Maybe sumfink like this?

https://en.wikipedia.org/wiki/ETS2101

...but who does phase I in France ;-) Sanofi?


Latest: Should treat Parkinsons, according to Le Monde...

Kindest regards, nobody
Helmut
Hero
Homepage
Vienna, Austria,
2016-01-15 17:48

@ nobody
Posting: # 15832
Views: 14,876
 

 Death in phase I cannabinoid?

Ho nobody,

» Maybe sumfink like this?
» https://en.wikipedia.org/wiki/ETS2101

Nope.

» ...but who does phase I in France ;-) Sanofi?

Follow my links. Bial, Portugal. According to their pipeline and this it was BIA 10-2474. Structure? No idea.

[image]All the best,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
nobody
Senior

2016-01-15 18:02

@ Helmut
Posting: # 15833
Views: 14,899
 

 Death in phase I cannabinoid?

Bingo!

Very sad day! Hope soon we will know what went wrong (study started last summer, 90 volunteers dosed yet, toxicity limit hit hard...)

Kindest regards, nobody
Ohlbe
Hero

France,
2016-01-18 13:42

@ Helmut
Posting: # 15836
Views: 14,711
 

 Structure

Dear Helmut,

» Structure? No idea.

Now available on Wikipedia.

Regards
Ohlbe
nobody
Senior

2016-01-28 15:29

@ Ohlbe
Posting: # 15882
Views: 13,776
 

 Structure

Wow, now it'S an N-oxide, originally Wikipedia provided the structure from this document:

http://www.freepatentsonline.com/20150174103.pdf

Kindest regards, nobody
Ohlbe
Hero

France,
2016-01-18 09:58

@ Helmut
Posting: # 15835
Views: 14,671
 

 Death in phase I cannabinoid?

Dear all,

» “Marisol Touraine, the French health minister, later said that the pill did not contain cannabis or its derivatives but acted on the body’s endocannabinoid system.”

According to information in the French press, quoting the sponsor, the compound is an inhibitor of the Fatty Acid Amide Hydrolase (FAAH), which metabolises endocannabinoids.

Regards
Ohlbe
nobody
Senior

2016-01-18 15:07

@ Ohlbe
Posting: # 15837
Views: 14,623
 

 Death in phase I cannabinoid?

http://www.sciencemag.org/news/2016/01/more-details-emerge-fateful-french-drug-trial

Multiple-dose trial with only compliance blood samples between 2nd and last day of dosing, so there will be limited data to figure out if something went wrong wrt PK... Will be hard to figure out what is going on here.

Very tragic.

Kindest regards, nobody
Ohlbe
Hero

France,
2016-01-22 17:18

@ nobody
Posting: # 15848
Views: 14,288
 

 Protocol

Dear all,

The French Agency has posted the trial protocol on its website.

The sponsor apparently refused them to publish the investigator's brochure and the IMPD.

Regards
Ohlbe
nobody
Senior

2016-01-23 18:37

@ Ohlbe
Posting: # 15849
Views: 14,222
 

 Protocol

Dose for muliple-dose part will be chosen based on single-dose results (0.25 to 100 mg). What was the starting dose of multiple-dose?

Kindest regards, nobody
Ohlbe
Hero

France,
2016-01-28 12:16

@ nobody
Posting: # 15874
Views: 13,739
 

 Protocol

Dear Nobody,

» What was the starting dose of multiple-dose?

According to information (in French) published yesterday by the French Agency, the first group received 2.5 mg per day, over 10 days.

Next groups: 5 mg, 10 mg and 20 mg, again once a day over 10 days.

Shit happened after 5 days in the 50 mg group.

Regards
Ohlbe
ElMaestro
Hero

Denmark,
2016-01-28 15:07

@ Ohlbe
Posting: # 15880
Views: 13,754
 

 Protocol

Hi all,

» According to information (in French) published yesterday by the French Agency, the first group received 2.5 mg per day, over 10 days.

This is a very interesting document.
In hindsight it must have been an extremely difficult decision towards the end of January 10, whether or not to stop the trial at that point. If the hospitalisation was due to the drug (drug product) or its dose, and this is a judgement made by the investigator or/and attending medic, then one can argue the trial could have been stopped immediately. With this being a fim-trial,it has to be enormously difficult to make that judgement in spite of all sorts of preclin/nonclin results, computer modeling, IMPD's etc. How can any person possibly know?
Here the trial was continued with the rest of subjects in cohort 5 dosed the day after hospitalisation of one subject from this cohort. I imagine the decision to continue after January 10 (whether actively taken or passively) will be challenged regulatorily, medically and legally in the aftermath of all this. It would not surprise me if EU regulators will update rules for sequential vs. serial dosing in fim-trials as well as rules for premature termination.

I am not much for the benefit of hindsight and I do not wish to point fingers. I am not saying anyone did anything wrong and I am not implying that any rules or principles relating to dir. 2001/20, ICH E6 or the Helsinki Decl. have not been observed. Hospitalisation of the other subjects in the group could have been the outcome as well even if they had not been dosed on January 11.

I could be wrong, but…


Best regards,
ElMaestro

- since June 2017 having an affair with the bootstrap.
nobody
Senior

2016-01-28 15:40
(edited by nobody on 2016-01-28 15:55)

@ ElMaestro
Posting: # 15883
Views: 13,748
 

 Protocol

"Half-life (persistence in the blood) of the drug in rats was 45 hours (oral) or 4 hours (i.v.) and in dogs it was 104 hours (oral) or 52 hours (i.v.)." Wikipedia, from protocol, p. 28

WOW! Values given for total radioactivity... apparently oral dosing results in some long-lasting metabolite?


"In the mouse, rat, dog and monkey, BIA 10-2474 undergoes extensive metabolism" ibid

Interesting. Details would be nice. Even on human microsomes and other in vitro stuff...


Experience in humans before this trial according to protocol: zero, null, niente.

Kindest regards, nobody
Helmut
Hero
Homepage
Vienna, Austria,
2016-01-28 17:10

@ nobody
Posting: # 15884
Views: 13,689
 

 FIM / FIH

hi nobody,

» Experience in humans before this trial according to protocol: zero, null, niente.

That’s why such studies are called First-in-man (or lately more “politically correct” First-in-human), right?

[image]All the best,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
nobody
Senior

2016-01-28 17:55

@ Helmut
Posting: # 15885
Views: 13,688
 

 FIM / FIH

Up to potentially toxic levels in single AND multiple dose AND including food effect. All in one trial. Without any knowledge on human metabolism. Metabolism elucidated on the fly throughout the study?

Kindest regards, nobody
nobody
Senior

2016-02-26 21:05

@ nobody
Posting: # 16033
Views: 12,510
 

 There is something rotten in the state...


Kindest regards, nobody
Ohlbe
Hero

France,
2016-02-27 05:49
(edited by Ohlbe on 2016-02-27 07:47)

@ nobody
Posting: # 16034
Views: 12,237
 

 Rotten or not rotten ?

Dear Nobody,

» This stinks.

IMHO what would stink would be not to have any dog die during the preclinical studies. It would mean that either the maximum tolerated dose was not reached, or some data were masked.

According to information since published in the French press, these dogs received 100 mg/kg/day during 3 months (i.e. about 1500 mg/day). The subject who died got 50 mg/day over 5 days. None of the dogs had neurological problems of the same type as the 5 subjects.

Regards
Ohlbe
nobody
Senior

2016-02-27 10:56

@ Ohlbe
Posting: # 16036
Views: 12,225
 

 Rotten or not rotten ?

The story would be more impressing if the data were available. I don't buy this without all the data, sorry. It is very interesting to read in one of the early press releases that everything was OK with the approval/oversight of this trial.

While everybody in this field who has done first in man simply shakes head about such toxicity not found in the preclinical assessment. If that was really the case then we have a black swan here and then it would be absolutely crucial to make all data available in the public domain.

This stinks. Errors have been made. What we see now is the usual cover-up.

Kindest regards, nobody
Ohlbe
Hero

France,
2016-02-27 14:00
(edited by Ohlbe on 2016-02-27 16:33)

@ nobody
Posting: # 16037
Views: 12,270
 

 Rotten or not rotten ?

Dear Nobody,

» The story would be more impressing if the data were available. I don't buy this without all the data, sorry.

I'd love to see a full picture too. Unfortunately Bial are not willing to see the data made public. At least they were shared with the other EU agencies and the FDA.

But I'm not impressed either by an article by a non-specialised journalist, in an opposition newspaper, trying to make a lot of fuss and pretending to see a scandal in something which is actually expected, in order to criticise the Minister of Health from the opposite party and the director of the French Agency appointed by her.

» This stinks. Errors have been made. What we see now is the usual cover-up.

Could be. I dunno. But political manoeuvres yes, very likely.

Regards
Ohlbe
nobody
Senior

2016-04-25 17:21

@ Ohlbe
Posting: # 16237
Views: 10,660
 

 Rotten..

Hi again!

Although the author doesn't really get the point in my opinion, nice to see I'm not alone with the assessment that the protocol was, ehhhmmmm, not really good.

http://onlinelibrary.wiley.com/doi/10.1111/bcp.12920/pdf

Would love to see the details, but I guess I would have to get a decent degree in Law and start a business as a product liability lawyer...

Kindest regards, nobody
nobody
Senior

2016-05-23 12:27

@ nobody
Posting: # 16351
Views: 9,621
 

 Blame game...

Hi again!

https://translate.google.com/translate?hl=de&ie=UTF8&prev=_t&sl=fr&tl=en&u=http://www.lemonde.fr/medecine/article/2016/05/22/essai-clinique-mortel-de-rennes-un-rapport-pointe-le-manque-d-information-des-volontaires_4924184_1650718.html

...looks like distraction from shortcomings regarding authorisations overlook of study, now responsibility handed over to the CRO. Design is OK, BUT... finally not OK, but ... somewhat OK.

In the end: WHAT caused the toxicity?

Kindest regards, nobody
nobody
Senior

2016-08-15 16:38

@ nobody
Posting: # 16552
Views: 7,428
 

 FDA: "unique toxiciy"

Hello again!

The FDA has some news on this

http://www.fda.gov/Drugs/DrugSafety/ucm482740.htm

... but no details at all. Any news from this heroic continent here?

Kindest regards, nobody
Ohlbe
Hero

France,
2016-01-29 18:30

@ Ohlbe
Posting: # 15894
Views: 13,623
 

 Chronology - English version

Dear all,

The French Agency has now published an English version of the chronology of events.

Regards
Ohlbe
Helmut
Hero
Homepage
Vienna, Austria,
2016-01-29 19:04

@ Ohlbe
Posting: # 15896
Views: 13,596
 

 Chronology - English version

Dear Ohlbe,

THX for keeping us informed. I agree with what ElMaestro posted before. The decision to continue cohort 5 on Jan 11th was a tough one and IMHO, more than questionable.

[image]All the best,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
Ohlbe
Hero

France,
2016-02-04 23:30
(edited by Ohlbe on 2016-02-05 16:23)

@ Helmut
Posting: # 15928
Views: 13,171
 

 Administrative inspection preliminary outcome

Dear all,

The interim report of the "Inspection générale des Affaires sociales" (IGAS, general inspectorate for social affairs) has been published today (in French). The IGAS is more of an administrative overarching inspection body, not specialists in clinical trials. However, their interim report occasionally refers to the interim report of the ANSM, the French competent authority.

To summarise:
  • no explanation was found so far regarding what happened...
  • no observation regarding the way an authorisation was granted to Biotrial to run Phase I studies (by the way, they don't recommend to suspend that authorisation)
  • the favourable opinion of the Ethics Committee and the authorisation by ANSM followed the French laws and regulations
  • some discussion on administrative aspects, some bullshit here and there.

» The decision to continue cohort 5 on Jan 11th was a tough one and IMHO, more than questionable.

IMHO that's indeed the most interesting part of the report (see from page 23, some chronology also on page 29). Basically:
  • the subject had some transient, non-specific and non-worrying signs from 9 AM on the Sunday;
  • after he woke up from an afternoon nap, the other subjects called a staff member around 18:30 (no detail given on the symptoms);
  • the MD on night duty examined him and called a subinvestigator. The decision to transfer the subject to the hospital was taken after further examinations and phone discussions. The subject was then immediately transferred;
  • at 20:40, the MD on night duty informed by phone the MD who was to administer the IMP on the next morning, that the subject had been hospitalised;
  • Monday at 07:55, the MD on night duty gave feed-back to the second MD, and informed him that he had refused the transfer of the subject from the hospital back to Biotrial during the night (no reason given in the report);
  • the remaining subjects were dosed;
  • then around 9 AM, a MD called the hospital to get some news regarding the status of the subject who had been hospitalised... So apparently, after dosing the other subjects.
Biotrial apparently say that they expected the subject to come back from the hospital on Monday morning (well, in a way that's understandable if the hospital tried to transfer him back during the night), and that they never received a call from the hospital to inform them that he was worsening.

The IGAS investigations are still ongoing. The ANSM inspection report has apparently been sent to Biotrial for their response, with some requests for additional information. But in any case, it looks like none of the two inspections will identify the root cause of the accident.

Other investigations are still ongoing - including those of the judges assigned to the case. The cops have probably seized the remaining IMPs and sent them to a lab for analysis. Maybe we'll learn more from this.


Edit: Biotrial apparently claim that the subject had his first brain MRI on the Monday at 9 AM, i.e. after the other subjects were dosed at 8 AM, and that they got the information at 10 AM that he had had a stroke.

Regards
Ohlbe
ElMaestro
Hero

Denmark,
2016-06-21 16:42

@ nobody
Posting: # 16433
Views: 9,055
 

 Re-consenting volunteers?

Hi all,

I am not a native French speaker but I think I sometimes understand a little bit of written French.

(and I am not too hot on Google translate)

Does the inquest into the Bial/Biotrial incident suggest that the volunteers should perhaps, possibly, maybe have been asked to re-confirm their consent after the initial SAE in their dosing group? I have no idea legally, but I am not aware of any clear clause in ICH E6 or Eudralex etc. that would require it. I think the need to re-consent is solely a matter of interpretation and that is sometimes a dangerous tool is the hands of people who look over the shoulder with little regard to the present.

Did I get the document right about re-consent? I foresee a lot of trouble if CROs in the future need to preemptively re-consent study volunteers. In the absence of firm specfic written guidance it will be very difficult to decide when a re-consent is justified and necessary.
e.g.
-When any SAE's occur? If no, which then?
-When any AE occurs? A broken toenail? Headache? Absence of info from a volunteer who has retracted her/his consent without telling why? Someone being discontioued by an investigator? Etc.

Is there a French guideline or legal document specifically discussing re-consenting?

Thanks for any input. As they say in France: Muchas gracias.

I could be wrong, but…


Best regards,
ElMaestro

- since June 2017 having an affair with the bootstrap.
Ohlbe
Hero

France,
2016-06-22 05:06

@ ElMaestro
Posting: # 16435
Views: 9,020
 

 Re-consenting volunteers?

Dear El Maestro,

» I am not a native French speaker but I think I sometimes understand a little bit of written French.

I am a native French speaker but there are a number of points in this report which I'm not getting either.

» Does the inquest into the Bial/Biotrial incident suggest that the volunteers should perhaps, possibly, maybe have been asked to re-confirm their consent after the initial SAE in their dosing group?

No, it does not suggest any such thing. It affirms it.

» Is there a French guideline or legal document specifically discussing re-consenting?

Not that I know of. Apart from the recent press releases of the Minister, of course :crying:.

If you want to practice your French, have a look at Biotrial's response to the initial inspection report. A "lost for lost", last pleasure kind of thing. You'll see for instance that in their initial report the inspectors made reference to a ministerial Order of 2006 on the notification of SAEs... which had been replaced by a new Order in April 2014. This gives some idea on how well these guys know and understand our laws and regulations governing clinical trials.

Regards
Ohlbe
nobody
Senior

2016-06-22 11:26

@ Ohlbe
Posting: # 16438
Views: 8,982
 

 Re-consenting volunteers?

» » I am not a native French speaker but I think I sometimes understand a little bit of written French.
»
» This gives some idea on how well these guys know and understand our laws and regulations governing clinical trials.

...if you outsource, you outsource, I don't think that the sponsor can be aware of all local regulations, the CRO should provide the sponsor in the protocol with all his obligations according to local laws. My opinion!

Kindest regards, nobody
Ohlbe
Hero

France,
2016-06-23 04:51

@ nobody
Posting: # 16447
Views: 8,966
 

 Re-consenting volunteers?

Dear Nobody,

» » This gives some idea on how well these guys know and understand our laws and regulations governing clinical trials.
»
» ...if you outsource, you outsource, I don't think that the sponsor can be aware of all local regulations, the CRO should provide the sponsor in the protocol with all his obligations according to local laws. My opinion!

"These guys" in my sentence above did not refer to either the sponsor or Biotrial, but to the IGAS inspectors who perpetrated this report.

Regards
Ohlbe
ElMaestro
Hero

Denmark,
2016-06-23 08:23

@ Ohlbe
Posting: # 16449
Views: 8,964
 

 Re-consenting volunteers?

Hello Ohlbe,

» "These guys" in my sentence above did not refer to either the sponsor or Biotrial, but to the IGAS inspectors who perpetrated this report.

I have a funny taste in my mouse.

Is this all about a minister trying to acquit organisations under her command by using buddies from an incomp sorry I mean independent organisation to examine the role of the adminstrative bodies that originally handled the trial paperwork, and to place the responsibility elsewhere?



PS: Hey where did 'strikethrough' letters suddenly go?!? Hötzi, you naughty boy, have you been messing up the board again? *sigh* What shall we do with you?

I could be wrong, but…


Best regards,
ElMaestro

- since June 2017 having an affair with the bootstrap.
nobody
Senior

2016-06-23 10:36

@ ElMaestro
Posting: # 16450
Views: 8,948
 

 Re-consenting volunteers?

works as expected, huh?

That's what I meant with "cover up" from the very beginning. Drop responsibility somewhere else, protocol might be fu** up, but in NO WAY the authorities were involved or could have stopped this.. NOOOOOWAAAAYYY

Kindest regards, nobody
d_labes
Hero

Berlin, Germany,
2016-06-23 11:31

@ ElMaestro
Posting: # 16452
Views: 8,923
 

 OT: strike

Dear ElMaestro,

» PS: Hey where did 'strikethrough' letters suddenly go?!? Hötzi, you naughty boy, have you been messing up the board again? *sigh* What shall we do with you?

Seems you have re-discovered the strike-through letters :cool:.

To demystify this for others:
durchgestrichen is coded with the tag [d].

Sometimes RTFM helps :-D.

Regards,

Detlew
Helmut
Hero
Homepage
Vienna, Austria,
2016-06-23 13:01

@ d_labes
Posting: # 16453
Views: 8,940
 

 OT: strike

Dear Detlew, ElMaestro & nobody

» » PS: Hey where did 'strikethrough' letters suddenly go?!?

Detlew got it right. According to TFM the BBCode is [d] (for “deleted”) since 2004. First use in post #15. The BBCode [s] was never implemented.

» » Hötzi, you naughty boy, have you been messing up the board again?

Nope. Last change was in April. I added [s]* for your convenience now. Heck, this is a forum not a bloody board.

» » *sigh* What shall we do with you?

Gimme a kiss?

» Seems you have re-discovered the strike-through letters :cool:.

Sorry, this was me. I edited ElMaestro’s post without giving an explanation.


  • Had to to edit some posts where [s] was used as an index in R-code.
    BBCodes are tricky. The forum forced me to start my loops in R with the index j instead of the more common i ’cause the former would render [i] to italics…
    See also this post.

[image]All the best,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
Ohlbe
Hero

France,
2016-11-03 12:21
(edited by Ohlbe on 2016-11-03 14:00)

@ nobody
Posting: # 16768
Views: 5,815
 

 Paper in the NEJM

Dear all,

Interesting paper in the NEJM.

Regards
Ohlbe
nobody
Senior

2017-06-09 10:01

@ nobody
Posting: # 17476
Views: 2,544
 

 Death in phase I cannabinoid?


Kindest regards, nobody
Back to the forum Activity
 Thread view
Bioequivalence and Bioavailability Forum | Admin contact
17,323 Posts in 3,705 Threads, 1,068 registered users;
27 users online (0 registered, 27 guests).

It’s easy to lie with statistics;
it is easier to lie without them.    Frederick Mosteller

The BIOEQUIVALENCE / BIOAVAILABILITY FORUM is hosted by
BEBAC Ing. Helmut Schütz
XHTML/CSS RSS Feed