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  1. #1
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    The ethics of human trials

    What a shocking incident in the UK with those six people who volunteered to be tested for that new cancer drug. It is hard to know all the facts; indeed, even the name of the exact company involved is hard to get for reasons of "commercial confidentiality". Surely, that's a pretty laughable excuse for secrecy now that the drug is absolutely useless!!

    I am sceptical about the ethical conduct of the experiments. Doctors never tell you about MIMS - a medical book in your local library that lists all possible side effects of prescribed drugs, even the rare and most injurious efefcts. So when there is research money at stake and a product cycle to meet then isn't there even less reason to inform the volunteer of anything potentially harmful. It seems pretty inexcusable to me that such a blatantly adverse reaction wasn't suspected when the technology today is sophisticated. Computer simulations and models provide more prognosticative data than rats ever did.

    While I am no lawyer I would expect this company to be taken to the cleaners in any lawsuit; when six people receive a lethal reaction it clearly isn't some idiosyncratic personal response.

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    Quote Originally Posted by qpawn
    What a shocking incident in the UK with those six people who volunteered to be tested for that new cancer drug. It is hard to know all the facts; indeed, even the name of the exact company involved is hard to get for reasons of "commercial confidentiality". Surely, that's a pretty laughable excuse for secrecy now that the drug is absolutely useless!!
    The company is called Parexel, a US company whose name is available in the general press, there's no secrecy. Because the facts are not known it would be wise not to jump to conclusions.

    I am sceptical about the ethical conduct of the experiments.
    Sceptical you may be but the ethical standards applied to the introduction of these kinds of medications into the human population, especially in the UK are very high, the penalties for not reaching these standards very severe.

    All drugs at some stage need to be introduced to human subjects in a controlled environment, otherwise no drugs would ever be available. Anti-cancer agents are initially 'trialled' on patients who are terminally ill and have no other recourse. Most of these patients are only too eager to volounteer because they usually only have weeks or months to live. They have little to loose in these situations and if the drug proved successful, much to gain. There is always risk as they will be the first human subjects to have tried these drugs, but hospitals employ teams and ethical supervisors in order to ensure the patients are fully informed. The relatives are usually brought into the decision unless the patient specifies otherwise. Nobody forces these patients into these trials, in fact demand is usually greater than supply.

    Doctors never tell you about MIMS - a medical book in your local library that lists all possible side effects of prescribed drugs, even the rare and most injurious efefcts.
    No, its top secret, I don't know how it got into your local library, that should never have happened.

    So when there is research money at stake and a product cycle to meet then isn't there even less reason to inform the volunteer of anything potentially harmful.
    Most drugs take 10 years and around $10m to get to market. Each trial stage is set by the overseeing body in that country. In Australia it's the Therapeutic Goods Association (TGA). All drug companies have to satisfy the TGA that every criterion is met. All drugs introduced into Australia must have gone through testing protocols in Australia. If you feel the standard is too slack, it's the TGA you need to advise. Maybe you should read their protocols before you pass judgement?

    It seems pretty inexcusable to me that such a blatantly adverse reaction wasn't suspected when the technology today is sophisticated.
    The therapy was a human monoclonal antibody that has been extensively tested in animals and had provoked no major reactions. From what I can gather, when humans were given the drug they developed allergic responses to the human protein. I suspect the patients were taken to the ICU as a precaution, 4 of the 6 left the ICU within 24hrs. Allergic reactions, although severe in this case, leave no long term legacy, the patients would make a full recovery. It's no different to an allergic reaction to penicillin.

    The fact they were taken to the ICU is a reflection of the strict safety precuations employed and available when these trials take place.

    Computer simulations and models provide more prognosticative data than rats ever did.
    Most drugs are designed on computers these days, but that's about as far as computers can take us. The rat shares enormous physiological simularities to the human, only the chimpanzee is superior - drug testing on chimpanzees is no longer permitted apart from exceptional circumstances.

    While I am no lawyer
    And I can see you're no doctor either.

    I would expect this company to be taken to the cleaners in any lawsuit; when six people receive a lethal reaction it clearly isn't some idiosyncratic personal response.
    I'm sure they'll be straight down to their lawyers when they're recovered.
    Last edited by Cat; 17-03-2006 at 09:00 PM.
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  3. #3
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    juxtapositions

    There is admirable restraint:

    The company is called Parexel, a US company whose name is available in the general press, there's no secrecy. Because the facts are not known it would be wise not to jump to conclusions.

    *******
    And then all your discretion goes down the plughole:

    I'm sure they'll be straight down to their lawyers when they're recovered.

    ********
    Unless you are employed in some capacity that is directly involved in this case, how can you hopw to know the drug's efefcts or the medical history of the 6 patients? To take the liberty of reaching the above conclusion without such knowledge is either foolhardy if you are not a doctor or grossly irresponsible if you do hold a medical qualification.

    In either case I can reach one conclusion only about you:

    you are an idiot.

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    Quote Originally Posted by qpawn
    Unless you are employed in some capacity that is directly involved in this case, how can you hopw to know the drug's efefcts or the medical history of the 6 patients?
    Because it was quoted in the Guardian newspaper, 4 had already been discharged from the ICU.

    To take the liberty of reaching the above conclusion without such knowledge is either foolhardy if you are not a doctor or grossly irresponsible if you do hold a medical qualification.
    Yes I am a doctor, and I also have a degree in immunology and have worked for 2 years on ICU's in the UK. I have been involved in these kinds of situations before and I know how the system works. I am also aware of how the press present these stories in emotive ways to capture the attention of people like yourself. Take a cold shower and cool off.
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    More details have emerged on the cases. 2 of the 6 remain on the ICU, one is in a coma and may not recover. They were all healthy volounteers, the comatosed patient only 21.

    It has not deterred volounteers for drug trials, thank goodness. The nos. have increased from 25/day to 90/day. From the Guardian;


    What sort of drug is it?
    TGN1412 is a class of drug known as monoclonal antibodies - genetically engineered versions of antibodies, the body's natural immune defences against infections. Monoclonal antibodies were hailed as miracle cures in the 1980s and 90s for their potential to attack disease without harming healthy cells. There are 19 monoclonal antibody drugs currently in use in the UK, including the breast cancer treatment Herceptin, and another 150 are currently in clinical trials, according to the Medical Research Council.
    How was it intended to work?
    The drug was being developed by German biotech company TeGenero for the treatment of chronic inflammatory conditions, including rheumatoid arthritis, leukaemia and multiple sclerosis. These conditions are caused by the body's immune system attacking itself.

    TGN1412 was designed to target the CD28 protein on a subset of immune system cells called T cells. The antibodies in the drug get into the bloodstream, seek out the immune cells, and then latch on to them. Most antibody treatments work by shutting down biological reactions, but TGN1412 is designed to do the opposite - activate the T cells. It was thought the drug would over-stimulate the rogue T cells, making them burn out and die.

    What might have gone wrong?
    Experts suggest that the adverse reactions occurred due to flaws in the clinical trial, the nature of the drug itself, or as a result of contamination.

    Problems with the tests
    Anne Alexander, a solicitor acting for one of the men on life support, said it was unclear whether successful experiments had been carried out on animals before the human tests took place. She said the drug company had said there was "an oversensitivity in monkeys" to the drug, and "a dog and some animals had died ... so they reduced the amount to humans".

    But the chief scientific officer of TeGenero, Thomas Hanke, said the drug had been tested on rabbits and monkeys with no "drug-related adverse events" resulting. The MHRA said the original pre-clinical data submitted by the biotech firm showed the drug appeared to have been properly tested on animals. The watchdog added that the dose given to the six men was 500 times lower than that administered in the animal tests. Saad Shakir, the head of the Drug Research Unit at Southampton University, said the adverse reactions suffered by the men appeared to be allergic or hypersensitive rather than dose dependent.

    Roberto Solari, chief executive of the MRC, said the six volunteers should not have been given the same dose of the drug at the same time. He said: "Not only had this drug never been tested in humans before, but no drug has ever been introduced into man that targets the CD28 protein on the surface of T Cells. I would personally have been cautious and dosed one person then waited a bit for any adverse reactions." But the MHRA said it had no problem with the men being given their doses simultaneously.

    The nature of the drug
    Another theory is that the drug functioned differently in humans than it did in animals. Experts say that animals involved in the trial may not have suffered adverse reactions because TGN1412's man-made antibodies are specifically targeted to affect specific human protein. Dr Solari said: "There isn't an intrinsic problem with monoclonal antibodies. The issue is the target of this drug, what the antibody attacks rather than the antibody itself." He said there could have been some "exquisitely human effect not picked up in animals" because the artificial antibodies were designed to only latch on to human protein. However, the MHRA said data provided by TeGenero appeared to show that only animals responsive to the drug's monoclonal antibodies were used in the tests prior to the human trial.

    Contamination
    Dr Shakir said contamination of monoclonal antibody drugs would be far easier because they are biological products. For example, a virus might have contaminated TGN1412 during the manufacturing process.

    What is the men's prognosis?
    It is difficult to predict but the signs are not promising. Relatives of one of the two men in a critical condition said he was unable to breathe unaided and doctors told them he could be in a coma for up to a year. The four men in a serious condition are showing signs of improvement. But all six are on organ support machines and are receiving steroids to suppress their immune systems. They have also received a number of blood transfusions in a bid to remove toxins from their bodies.
    This doesn't make sense - there are no 'organ supprot machines' as such. If they were on ventilators they would still be on ICU. They may be referring to dialysis perhaps, or it may simply be a misinterpretation

    How might this affect drug trials?
    There are fears this case could deter people from volunteering to test new drugs, even though scientists and the pharmaceutical industry stress that this disastrous trial is exceptional. Brian Iddon, a member of the Commons' science and technology select committee, said that clinical trials in the UK were strictly regulated. Simon Festing, director of the Research Defence Society, which advocates animal research in medicine, noted there had only been one death in a clinical trial in this country in the past 25 years.

    How might it affect animal testing?
    Dr Festing said that if the MHRA found the problem lay with the intrinsic nature of TGN1412, there might be a case for new guidelines to govern clinical trials of biological drugs. It might even be the case that animal testing would not be appropriate for some drugs designed to specifically target human proteins. He said: "If they were shown not to work then we wouldn't want to use them." But Dr Festing added that it might be possible to genetically modify animals to respond to such drugs in the same way as humans. Dr Solari, of the MRC, added that without animal testing a lot of humans would be killed in clinical trials.
    Last edited by Cat; 19-03-2006 at 08:32 AM.
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    of course not

    No. It hasn't deterred anyone from being a guinea pig. And if healthy people are scared off volunteering you can always find some poor, cancer-stricken bastard who will try anything for a possible "cure". That's a great statistic that is: one death in 25 years of human trials. So if you are permanently injured, blown up like the elephant man, develop a rash that leaves you looking like a 3rd degree burn victim etc, none of this stuff matters a jot. Actually, I suppose it doesn't matter. Just make sure that your volunteers are poor middle class blighters who won't be able to sue the juggernaut drug company. That or slap the volunteer with a caveat emptor form as they are about to be injected with a drug.

    If your intent was to reassure me about the ethics and/or safety of human drug trials you have had the opposite effect; I am astonished at your naive insensitivity towards the complex ethics of thses trials. You should know - I hope - that someone in a state of terminal illness is easily exploited by false hope and claims. The doctors who offer to give such people trials have a moral duty to not put any pressure on someone so vulnerable: that is, pressure either overt or subtle. There is also the issue of financial inducements for participating in trials. The policy here in Australia is very different from that in the UK; here we offer a nominal reward to cover the time and inconvenience for the patient. It appears that in the case of thses 6 people in the UK that they were offered a sizeable financial incentive to volunteer: an ethically dubious enticement I would say.

    Please get a good book on medical ethics such as anything by James Rachels. Then come back to me.

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    Quote Originally Posted by qpawn
    No. It hasn't deterred anyone from being a guinea pig.
    As I say, many people are happy to try a new treatment, when there is no hope to be found elsewhere. I think we'd all grasp that opportunity.

    And if healthy people are scared off volunteering you can always find some poor, cancer-stricken bastard who will try anything for a possible "cure".
    Presumably healthy people volounteer because they feel they are doing some good in the world. What's so wrong with looking for a cure?

    That's a great statistic that is: one death in 25 years of human trials.
    Yes it's a bloody amazing record.

    So if you are permanently injured, blown up like the elephant man, develop a rash that leaves you looking like a 3rd degree burn victim etc, none of this stuff matters a jot. Actually, I suppose it doesn't matter. Just make sure that your volunteers are poor middle class blighters who won't be able to sue the juggernaut drug company. That or slap the volunteer with a caveat emptor form as they are about to be injected with a drug.
    As I say, the TGA sets the guidelines in Australia. The drug companies comply with our guidelines. I would suggest you read the TGA's code of practice before you make such judgements. Maybe you have ideas on how it could be improved?


    If your intent was to reassure me about the ethics and/or safety of human drug trials you have had the opposite effect; I am astonished at your naive insensitivity towards the complex ethics of thses trials.
    Its clear to me you know nothing of the process involved. Your arguments wreak of ignorance and you pass generalised judgements on a system that is widely held to be very reputable within the industry. Rather than making blanket statements, perhaps you should consider any specific issues raised by this case to make detailed points, then you would seem more credible.

    You should know - I hope - that someone in a state of terminal illness is easily exploited by false hope and claims. The doctors who offer to give such people trials have a moral duty to not put any pressure on someone so vulnerable: that is, pressure either overt or subtle. There is also the issue of financial inducements for participating in trials. The policy here in Australia is very different from that in the UK; here we offer a nominal reward to cover the time and inconvenience for the patient. It appears that in the case of thses 6 people in the UK that they were offered a sizeable financial incentive to volunteer: an ethically dubious enticement I would say.

    Any trial would have to satisfy the UK Ethics Committee before it could be sanctioned, so presumably they would have been satisfied with the trial design and the available data on the drug. The patients were paid about $4000 for their participation, about a morning's pay for any self-respecting Dr. You're right that sizeable inducements are ethically challenging, but there are strict guidelines on what can and can't be offered, even in the UK!!

    Someone, somewhere at sometime must be the first human to take any drug. There are 3 logical scenarios relating to the introduction of new drugs, which would you prefer?

    1. Drugs are introduced wholesale to human populations without restrictions.

    2. Drugs are introduced in restricted fashion to a small number of humans according to a strict set of criterion. After a period of surveillance, the number of individuals included is initially increased and then finally if no significant problems arise, the drug is made available to the wider population, but under a probationary period of 1 year (drug trials and current practice).

    3. No drugs are ever given to humans.
    Last edited by Cat; 19-03-2006 at 03:19 PM.
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    Quote Originally Posted by qpawn
    I am sceptical about the ethical conduct of the experiments.
    $10 says that the actual dose given was wrong, or the wrong stuff all together

    I reckon 10^3, milligrams instead of micrograms or a wrong lable

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    If you think this drug trial is bad compare it with this.

    http://thetalkingdrum.com/tus.html

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    Quote Originally Posted by Matthew Sweeney
    $10 says that the actual dose given was wrong, or the wrong stuff all together

    I reckon 10^3, milligrams instead of micrograms or a wrong lable
    You could be right, but I think it sounds like an Immune Complex reaction - in other words the recipients antibody's attacked the monoclonal antibody, creating large protein complexes that accumulated in the end organ capillaries.

    There is also a suggestion that the monoclonal antibody may have cross-reacted with other human antigens.
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    Cat, I admire your debating style. To the point, non-emotive, informed, avoiding generalisations. Others can take note.

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    Quote Originally Posted by WhiteElephant
    Cat, I admire your debating style. To the point, non-emotive, informed, avoiding generalisations. Others can take note.
    Cheers
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    you missed Cat's insult?

    I am not a fan of Cat's debating "style": it included an unnecessary go at me for not being medically qualified. I feel sorry for anyone such as White Elephant who finds any of Cat's arguments convincing.

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    Quote Originally Posted by Cat
    You could be right, but I think it sounds like an Immune Complex reaction - in other words the recipients antibody's attacked the monoclonal antibody, creating large protein complexes that accumulated in the end organ capillaries.

    There is also a suggestion that the monoclonal antibody may have cross-reacted with other human antigens.
    OH! I didn't know they were using Mabs. I had better withdraw my $10 bet. I withdraw my bet offer now. If they were getting Ab agragation then we would see ischemic skin lessions. I read they were/are purple. Jeez, they are likely to have brain damage too - after all it appears that every capillary bed was effected.

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    Quote Originally Posted by qpawn
    I am not a fan of Cat's debating "style": it included an unnecessary go at me for not being medically qualified. I feel sorry for anyone such as White Elephant who finds any of Cat's arguments convincing.
    I'm not having a go at you, it's simply that you've painted the situation in very black & white terms. Let me tell you that everyone involved in that trial, from the doctors, nurses and the pharmacists would be feeling absolutely devastated about what has happened.

    Nobody goes into this profession with the intent to do harm. Things go wrong, people make mistakes and sometimes doctors get sick & do crazy things, but generally most people are deeply concerned for the welfare of their fellow man.

    Don't forget I'm a health consumer too, and when things go badly wrong its absolutely right to ask searching questions. But you must understand the mechanics of how the system works in order to ask the right questions.

    I think most doctors have had sleepless nights worrying about the well-being of their patients. De-humanising doctors and Pharmaceutical companies makes good reading but will never provide real solutions.

    Take the case of Jayant Patel - he was vilified by the press, scapegoated by the hospital and Peter Beattie. The reality was that he was brought in to the country by Queensland Health who were trying to cut costs and take shortcuts. He was placed in a position of responsibility for which he was unqualified, given inadequate guidance and support then left to hang. He was a symptom of failed management practices and a widespread malaise within Queensland Health.

    Money is now pouring in to Queensland Health & Queensland Hospitals like never before. 2 new medical schools have opened in Queensland and new contracts are being developed with visiting specialists. Patel has changed everything, there's now a chance that things might get better, he should be given a medal!

    It's so easy to point the finger, there must be someone to blame, but issues are have many facets. Fools rush in where Angels fear to tread!

    6 of the top 10 most profitable companies in the world are drug companies, the profits they make are scandalous. Just like you, I feel the pinch from that, but let's look in the right places for the answers.
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