14 ms·
French drug trial leaves six hospitalized, one brain-dead
- epmatsw 11y agoWhile 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 11y agoIt'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 11y agoOr 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/default.htm http://www.fda.gov/Food/RecallsOutbreaksEmergencies/Recalls/... 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!
- patrickaljord 11y ago> 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. This is France we're talking about here, we are one of the most regulated country on the planet, this includes FDA like institutions. Still, this could happen anywhere. Also, as has been pointed elsewhere, too much regulation can make people die that could have benefited from the a cure, except we don't notice these death.
- epmatsw 11y agoRight, it seems like this is a tragic success of the process. Without a body like the FDA or France's equivalent enforcing rigorous trials, this would not be 6 people who opted in, this would be hundreds or thousands of sick people who were harmed. But yeah, striking the balance between progress and safety is tough. It's just sort of comforting to see a tragedy minimized by the controls we've put in place.
- magicmu 11y ago"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.
- eterm 11y agoThat's referring to a previous drug trial.
- deleted 11y ago[deleted]
- colanderman 11y agoThat paragraph is referring to a previous incident. The current incident occurred in France in behalf of a Portuguese firm.
- lemmings19 11y agoThe last two paragraphs are in reference to a separate trial. More info on that trial: https: //en.m.wikipedia.org/wiki/TGN1412
- pavedwalden 11y agoDon't feel bad, the article was a little unclear. I had to backtrack to figure out that the penultimate paragraph signaled a change in topic.
- deleted 11y ago[deleted]
- graeham 11y agoA 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.
- kauffj 11y agoThe 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.
- fixermark 11y agoThe solution may very well be more testing, control, and regulation. But there's a difference between minor tweaks to address the root causes of this issue (hypothetical: maybe the drug got contaminated in transit and post-shipping verification of contents needs to be done) and a "Shut it down, shut it all down" reaction. To draw a thin (but perhaps appropriate analogy): after the hijackings of airplanes on September 11th, the United States responded by expanding the air marshall program, significantly jacking up security and restrictions on passengers, and putting combination locks on airplane cabins. Only the last policy, I think, is actually necessary to address what happened on September 11th, and it's all they should have done.
- mkaziz 11y agoPersonally, I like the idea of air marshalls as well. It makes feel safer while flying. The TSA, on the other hand, definitely makes me feel less safe.
- richmarr 11y agoInterestingly air marshalls get arrested more frequently than they make arrests (as of 2010 at least). https://www.schneier.com/blog/archives/2010/04/the_effectivene.html https://www.schneier.com/blog/archives/2010/04/the_effective...
- ared38 11y agoI hate how politicians pander to the base with vague promises to increase or decrease regulation instead of debating to find which regulations are the most effective. Same situation for welfare programs, use of military power overseas, and taxation. There are undoubtedly better ways to use or collect the resources government currently has or even do more with less but they are never considered.
- xiaoma 11y agoSeeing 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 11y agoThere are plenty of stories published with exactly that message. Granted, they might not be exciting, but hit pieces are fairly common.
- tokenadult 11y agoThis 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/2eb51e2860ef54d218ce5ce19abe6a59/dc_biodemography_of_human_ageing_nature_2010_vaupel.pdf http://www.demographic-challenge.com/files/downloads/2eb51e2... [2] 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 http://www.slate.com/articles/health_and_science/science_of_...
- refurb 11y agoI 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%.
- lemmings19 11y agoHere 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
- rplnt 11y agoThis (HN) title is incorrect as it would make 7 "affected" instead of 6 as is written in article.
- ajb 11y agoOne 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.
- cowsandmilk 11y agoThere 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.
- ad-hominem 11y agoThe six men received the drug several times, starting on Jan. 7. The first symptoms appeared in one man on Sunday; he was quickly hospitalized, and the other men followed. The trial was halted the next day. They began receiving the drug on January 7, but no symptoms of a problem appeared until this past Sunday.
- wins32767 11y agoIt could well be a trial where they gradually increase the dose to find out what a safe dose is.
- csours 11y agoThe 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
- deleted 11y ago[deleted]
- awalton 11y agoI 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-bialessai-therapeutique/ http://www.breizh-info.com/2016/01/15/rennes-biotrial-biales... 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 11y agoIn 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.
- gregmac 11y agoTGN1412 was a different trial that happened in 2006: it's mentioned in the article as a similar incident because it hospitalized six men.
- cstross 11y agoNote 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 11y agocannabinoids 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?
- Aissen 11y agoFYI, 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-therapeutique-a-rennes-un-volontaire-en-etat-de-mort-cerebrale_4848001_3224.html http://www.lemonde.fr/societe/article/2016/01/15/essai-thera...
- sjg007 11y agoSeems weird to do a Phase I trial in healthy volunteers for a monoclonal antibody targeted to Parkinson's.
- sp332 11y agoPhase I is for safety. And it's hard to separate the effects of the drug from other health effects if the patients aren't healthy to begin with.
- chrisseaton 11y agoThis is the whole point of a Phase 1 trial. https://en.wikipedia.org/wiki/Phases_of_clinical_research#Phase_I https://en.wikipedia.org/wiki/Phases_of_clinical_research#Ph...
- sjg007 11y agoYou 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 11y agoPerhaps 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?
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- jhartmann 11y agoSome information about the trial seems to be here: http://www.breizh-info.com/2016/01/15/rennes-biotrial-bialessai-therapeutique/ http://www.breizh-info.com/2016/01/15/rennes-biotrial-biales...
- mrfusion 11y agoKeep 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.
- dawnbreez 11y agoWhat was the drug?
- TacticalMalice 11y agoSome investigation of recent patents by Bial points to a probable candidate http://cdsouthan.blogspot.nl/2016/01/the-unfortunate-case-of-bia-10-2474.html http://cdsouthan.blogspot.nl/2016/01/the-unfortunate-case-of...
- dawnbreez 11y agoSo 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.
- hyperliner 11y agoCan 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.
- graeham 11y agoIt simply get absorbed in the gut (like food or all medicines), into the blood. There is a 'blood-brain barrier' that many things cannot cross, but far from all. Painkillers, caffine, LSD, and other psychoactive drugs all cross this barrier by definition. In terms of damage, there are many possible mechanisms once in the actual brain tissue. Quite often drugs would act on a receptor on a cell, which would change how the cell operates in some way, such as by inhibiting an ion channel. https://en.wikipedia.org/wiki/Neurotoxin https://en.wikipedia.org/wiki/Neurotoxin
- jo909 11y agoNot 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 11y agoSomewhat 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.)
- TheOtherHobbes 11y agoThere are many ways to cause brain damage, e.g. increased blood pressure leading to a stroke localised inflammation of brain tissue (which can be caused by an autoimmune response) oxygen deprivation enzyme degradation, where an external chemical blocks some of the chemical processes that keep brain cells working (drinking mercury will do this) The second one seems to have happened here. The may have drug triggered a wildly excessive autoimmune response called a cytokine storm, which is the immune system's equivalent of a firework display where everything is launched at the same time. This basically poisons you from the inside in various colourful and unpleasant ways. There's nothing about oral ingestion that makes it more or less likely to cause brain damage. Many chemicals can survive stomach acid and pass into the blood stream. The drug on trial was one of them.
- milkcircle 11y agoJust 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.
- intrasight 11y agoAre 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 11y agoParkinson'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.
- jonlucc 11y agoYes, phase 1 is to ascertain if the drug is safe in healthy patients. These people opt in for these studies.
- icegreentea 11y agoPhase 1 is typically done to determine dosing and side effects. It's more difficult to get this information from unhealthy subjects - more confounding factors.
- jszymborski 11y agoWhile 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.
- dlandis 11y ago> What makes this unprecedented, imho, is that so many died. No one died from this trial.
- tremon 11y agopeople 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 11y agoYou 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.
- trhway 11y ago>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 11y agoIt'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.
- thrownunder 11y agoI 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 11y agoThere's speculation the structural family was disclosed in Bial's patent application http://www.freepatentsonline.com/20150174103.pdf http://www.freepatentsonline.com/20150174103.pdf
- tacon 11y agoWhen 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?