Clinical Trials...More caution maybe?

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I don't know how many of you heard about a pharmacokinetic drug trial that went hideously wrong a few years ago? Well at the moment I am working in Statistical Reporting in a pharmaseutical company in Basel called Novartis, I'm writing for M&S (modelling and simulation) and there is an awful lot of regulations and rules when doing toxicology experiments. The amount of steps before it even get's near human patients is extreme! First you find out the amount of dose for the effects to "just" become visible in a rat or something, then do some maths to convert to human equivalent by body mass and protean count, then do find the most appropriate species to work from (most similar in terms of this particular treatment) then apply a safety factor of 10 fold (give a tenth of the animal dose to the human patient) and finally increase the dose gradually all the while being very careful because the adverse effects of a drug, are rarely linear, and not always as predictable as one might think, (take MDMA for example, nothing then half an hour later...wheeeee!)
But even despite all these safety procedures, there was still an incident in which 6ish people nearly died, and that was with 500th the dose, that was utterly fine in a small dog! Amazing! What I found interesting though is that they gave all 6 people the drug (2 the placebo) and so all 6 nearly died. If they had given the drug one at a time, then only the first person would nearly die, which still sucks of course but the point is how where they to know?

So what do you think? Should volenteers go one at a time in future?

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@dawoel,

Thanks very much for the post, and I (as a medicine person) appreciate having your perspective on this here.

To answer your question, we need more information, such as the trial design, the power analysis, the phase of the trial, and the statistical significance of the adverse events.

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@dawoel,

Of course there is the aspect of perhaps we shouldn't compare reactions in animals to humans. Hmmm? That could have something to do with it. Just a thought.

William

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@dawoel,

Indeed, no two species have identical physiologies. The problem is, if not animals then what? I'm not sure you would be aloud to take part in an experiment that says "ok, we have never put this drug in a living organism before, we think it will do x, but we have no idea how much will do it, nor do we know anything about the side effects besides our prediction from the pharmacology board, but thats all just theoretical we have no evidence, in other words, even the smallest dose of this stuff might kill you, we just don't know!"
Now animals are not perfect because they are different biologically, but they are at least better than plants, lol. Also, though it sounds callous (sorry animal rights guys!) a rat is much easier to replace. I gather more similar species like other apes are massively expensive too. There ARE guidlines mind, they don't do experiments on animals to see just how much they can take anymore, that's cruel.

To answer your statement William, yes, your right, after all, 6 nearly died on 500th the dose that was fine in a small dog, animals are not people so this is an issue. But would you rather put the origional dose in a human strait off and have all of them die?

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@dawoel,

William;75315 wrote:

Of course there is the aspect of perhaps we shouldn't compare reactions in animals to humans. Hmmm? That could have something to do with it. Just a thought.

You need to do animal trials before you do human trials. While there are differences, there are many good animal models of various disease processes. Animal studies allow you to control the experimental conditions much better than in humans, so you can get preliminary info about efficacy and toxicity. Many drugs have been scrapped because of animal toxicity. It doesn't prevent one from having to do a clinical trial in humans, but it's a necessary first step.

I'm not clear on the original concern here. You need to tell me about the study design, the denominator, the power analysis, and the circumstances of the death (you haven't even said if it's from drug toxicity versus from the underlying disease).

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@dawoel,

Ah yes sorry...The 6 individuals where all healthy volenteers, I can't remember what the drug was sorry, all I remember was that they deemed the dog results most safe to use as a basis for their human experiments, but just to be safe, because it was quite a toxic drug, they used 500th the dose that was fine in the dog. 6 people where given this dose and two the placebo. & all the 6 nearly died. My concern was, why where they all done at the same time, and thus nearly killed all of them, when, if they had gone one at a time, they would notice the problem in the first one and then spare the other 5. I don't know the details of the experiment such as denominator or power analysis or symptoms, only that it went hidiously wrong, which, serves to demonstrait just how dangerous new drugs can be.

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@dawoel,

Sorry, I don't have the answer to that. But when we examine the minds ability to do literally wonders along with good nutritious food and homeopathy; perhaps the answers lie there somewhere. IMO, we are a long way from understanding the human body and all it's processes that define it's innate perfection. Pharmaceuticals are IMO quick fixes and there is no way we will ever know the long range affects of these "band-aids" we are using we call medicine. The invasion of one species to determine the workings of another is "voodoo" medicine IMO. But like you, I know of any other alternatives that will fall in favor with those who profit from these "voodoo" elixers we concoct.
In truth I can't argue in that these medicines are "keeping me alive". To that extent, i am grateful, but are they the answer? I think not. There is a lot we need to learn about what "do not disturb" truly means so we can get to those "natural solutions" that I feel will solve all our ills. How long that will take? Good question. Let's only hope we can learn from our errors and one of the biggest was opening up the first human to see what makes it tick. I honestly think when we stop tampering with the human body, it is fully capable of "healing itself" genetically, mentally and physically. IMMHO.

William

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@dawoel,

Hi,

My viewpoint:

1) The whole basis of the trials are flawed.

a) They ignore the fact that each individual is unique. That the cause of each health problem may be unique. That the way to cure may be unique for each individual.

b) They seek a substance that has a substantial effect on a large number of individuals within a defined group. The objective is not to achieve cure - but to achieve an effect. The effect is often extremely suppressive and can cause a huge rebound effect that creates even more health problems in an individual.

2) The trials are far too short in duration. Long term side effects are not well understood.

3) Trials are funded by and performed by companies and individuals that stand to benefit from a positive results. Often, studies are suppressed that do not yield desired results.

4) Conflicting studies are quite common. Often drugs are accepted in one country but not another. Does science change as it crosses borders? Does science change over time? The subjectivity of all trials has not been questioned enough in my opinion.

So how is that for starters? Smile

In my own opinion, the fatal flaw of trials is the massive assumption that a single substance can be found that will cure for a massive number of individuals. My own experiences, observing my peer group in their 50s and 60s, walking around with shopping bags of pills, I sense that this assumption is not a good one to make.

Rich

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@dawoel,

dawoel;75333 wrote:

6 people where given this dose and two the placebo. & all the 6 nearly died. My concern was, why where they all done at the same time, and thus nearly killed all of them, when, if they had gone one at a time, they would notice the problem in the first one and then spare the other 5. I don't know the details of the experiment such as denominator or power analysis or symptoms, only that it went hidiously wrong, which, serves to demonstrait just how dangerous new drugs can be.

So they weren't really close to doing a full clinical trial, then.

The problem is that if you give it to one at a time, you have no idea whether a subsequent event is related or not. Even with 6 it's hard to tell.

They need to go back to the drug and figure out if there's some contaminant or manufacturing problem, or if it's the drug itself. If they all nearly died of bacterial sepsis within a day of getting the drug, it might have been contaminated with something.

---------- Post added 07-06-2009 at 11:31 AM ----------

richrf;75340 wrote:

Hi,

My viewpoint:

1) The whole basis of the trials are flawed.

This wasn't really a trial, certainly not a full one, so it's not a fair criticism. It was a pilot study of safety. The question is is this drug safe. The answer is no, infact no within one dose.

Your argument that all drugs are bad is leading you to cast general aspersions at specific discussions.

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@richrf,

richrf;75340 wrote:

Hi,

My viewpoint:

1) The whole basis of the trials are flawed.

a) They ignore the fact that each individual is unique. That the cause of each health problem may be unique. That the way to cure may be unique for each individual.

Rich

I am certainly happy that you had no say in the clinical trials that led to small dose aspirins being given to people to prevent blood-clots and heart attacks. You would have been telling those who conducted the trials that "each individual is unique" and the "the cause of each health problem, and the cure may be unique". As a consequence, lots of heart attacks that did not occur would have occurred.

Happy that rationality reigns.

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@dawoel,

There is a statistical measure often used in clinical trials called the "number needed to treat"

Number needed to treat - Wikipedia, the free encyclopedia

It's basically the reciprocal of the change in absolute risk, and it tells you how many people need to be given a certain therapy to prevent one bad outcome.

If you can demonstrate that a cheap, safe therapy like aspirin can prevent one recurrent heart attack for every 100 or 1000 persons treated, then that is highly effective and can only be demonstrated with a trial.

And since aspirin is generic, one can hardly blame meddlesome drug companies for a trial like that.

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@dawoel,

Extremely informative, as always. More facts and logic, less vague and empty speculation. A crying need in philosophy as everywhere else.

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@kennethamy,

kennethamy;75428 wrote:

I am certainly happy that you had no say in the clinical trials that led to small dose aspirins being given to people to prevent blood-clots and heart attacks. You would have been telling those who conducted the trials that "each individual is unique" and the "the cause of each health problem, and the cure may be unique". As a consequence, lots of heart attacks that did not occur would have occurred.

Happy that rationality reigns.

The basis is flawed - until we allow for, and do not interfere with, humans getting to die during experiments. This experiment showed that 500th the small dog dose is lethal to adult humans, thought they did not intend to find that out.

1 Reply

@memester,

memester;75680 wrote:

This experiment showed that 500th the small dog dose is lethal to adult humans, thought they did not intend to find that out.

The experiment MIGHT have shown that, but it might not. Remember that the numbers are extremely small, and we don't have ANY information about who these patients were. Were they healthy controls? Were they patients with out-of-hospital cardiac arrest? Was it the drug or was it an underlying disease, and the small numbers prevent discernment of patient baseline factors? Was it the drug or was it an inert component?

1 Reply

@Aedes,

Aedes;75683 wrote:

The experiment MIGHT have shown that, but it might not. Remember that the numbers are extremely small, and we don't have ANY information about who these patients were. Were they healthy controls? Were they patients with out-of-hospital cardiac arrest? Was it the drug or was it an underlying disease, and the small numbers prevent discernment of patient baseline factors? Was it the drug or was it an inert component?

I think it did show it; are they about to give a 7th person 1/500 the small dog safe dosage ? :bigsmile:

No, because now they know better - not with different inert components, not with normal and healthy humans, not with any of your objections considered as possibilities...it just wouldn't be done, because now we KNOW better. The study showed that, quite successfully.
It will never be repeated at that level, so we know it as well as we will ever know it.

Perhaps later they might discover that if they gave bicarb as well, it is not toxic to humans at even ten times the small dog dosage. Nevertheless, what they know right now, is that what they did kills adult humans, assuming that there are no complicating circumstances such as them all being patients with similar pre-existing conditions. Even all being over 100 likely wouldn't result in that mortality rate.

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@dawoel,

dawoel;75302 wrote:

I don't know how many of you heard about a pharmacokinetic drug trial that went hideously wrong a few years ago? Well at the moment I am working in Statistical Reporting in a pharmaseutical company in Basel called Novartis, I'm writing for M&S (modelling and simulation) and there is an awful lot of regulations and rules when doing toxicology experiments. The amount of steps before it even get's near human patients is extreme! First you find out the amount of dose for the effects to "just" become visible in a rat or something, then do some maths to convert to human equivalent by body mass and protean count, then do find the most appropriate species to work from (most similar in terms of this particular treatment) then apply a safety factor of 10 fold (give a tenth of the animal dose to the human patient) and finally increase the dose gradually all the while being very careful because the adverse effects of a drug, are rarely linear, and not always as predictable as one might think, (take MDMA for example, nothing then half an hour later...wheeeee!)
But even despite all these safety procedures, there was still an incident in which 6ish people nearly died, and that was with 500th the dose, that was utterly fine in a small dog! Amazing! What I found interesting though is that they gave all 6 people the drug (2 the placebo) and so all 6 nearly died. If they had given the drug one at a time, then only the first person would nearly die, which still sucks of course but the point is how where they to know?

So what do you think? Should volenteers go one at a time in future?

I think it was more the poor enforcing of safety from the company, that wanted to cut corners. So Imo the procedures are fine, just punish the greedy companies.

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Clinical Trials...More caution maybe?

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