Placebo-controlled clinical trials

[Sarkus]

Just saw this on another thread, which got me thinking...

https://www.cnn.com/2021/12/14/health/pfizer-paxlovid-pills-covid-treatment/index.html

Extract
After a month of follow-up, the study found five hospitalizations and no deaths among 697 people who received the drug within the first three days of symptoms. Among 682 who received placebo, 44 were hospitalized, including 9 who died. All of the adults in this study were unvaccinated.

I have always found there to be something unethical about using placebos in clinical trials. There is surely already a wealth of data for comparison purposes for those that don't get a drug at all, so the only question is how one benchmarks against a placebo drug. Well, surely this can be done when there simply is no genuine drug up for trial?
I.e. you already know what the benchmark is for those not receiving either a placebo or the trial-drug.
So rather than testing Trial-Drug A v Placebo B, you separately test, before there is any genuine trial drug available: No Drug v Placebo B, while the patient thinks that the Placebo is a genuine drug - i.e. the same way that they would in a normal trial these days. Noone is deprived of an active/genuine trial-drug, as it doesn't yet exist.

When the new drug comes up for trial, the only thing to consider is how effective it is. We already have the benchmark of no-drug and of placebo-drug, so why not give the trial drug to everyone in the test group.

As it is, we effectively have 9 people (in the case above) that may not have died had they received the trial drug. And that's difficult to comprehend when I think the placebo effect can be separately understood and without withholding any genuine drug.

Sure, everyone who agrees to partake in these trials are aware that they may only get a placebo, and accept the risk for the greater benefit. But, as in this case, people can die that otherwise don't need to. And that just doesn't sit right with me.

Thoughts?

 

[Michael 345]

Thoughts

Agree. Placebo is the equivalent of doing nothing

Check next post

 

[Michael 345]

UK scrambles for booster shots and tests amid fears of Omicron 'tidal wave'

https://www.cnn.com/2021/12/14/uk/uk-covid-omicron-booster-shots-tests-gbr-intl/index.html

 

[sculptor]

Do not discount the psychosomatic effect too readily.

 

[Michael 345]

psychosomatic

Sorry cannot psychosomatic away a virus

Pretty sure I have read some testing of medications has been so obvious helping in its early testing phase testers have done away with the test group and started them on the medication also

 

[C C]

Do not discount the psychosomatic effect too readily.

When it comes to treatment of pain relief, mental health issues, etc... The beliefs or expectations of a patient can cause them to either exaggerate or disparage the effectiveness of a new drug. As well as even produce measurable results (here with respect to the placebo) not dependent upon reported perceptions, like lowered blood pressure.

But for life-threatening diseases/conditions, having a comparison for detracting the brain's contribution to personal assessment of how well a drug works may arguably be superfluous.

Heh. I take that back. If a patient given a placebo has great confidence in the fake version of the drug, then that might cause them to delay going to the hospital or not at all -- plus anything else critics could discern or conceive as a factor.[1] If the evaluators can also subtract those potential contributions from the patient's expectations about the real drug, then I suppose that might avoid some skewered assessments about it.

- - - footnote - - -

[1] The delay making the ailment worse, and increasing risks.

 

[Michael 345]

The delay making the ailment worse, and increasing risks.

A possible (in truth highly unlikely)

No way of knowing if you have been given placebo or not

For stuff like pain relief or sleeping tablets fine have a control group

Virus stuff affecting the immunity system a psychosomatic response to produce more antibodies very very questionable

 

[billvon]

We already have the benchmark of no-drug and of placebo-drug, so why not give the trial drug to everyone in the test group.

Unfortunately you have the no-drug vs placebo-drug data taken at a different time in the pandemic (if you're referring to a drug/vaccine for COVID for example.) You therefore have data on no drug vs. Delta, and data on drug vs. Omicron. What if the drug shows that serious outcomes are reduced (less death) but there are far more infections with moderate (i.e. symptoms that keep people home) outcomes? Is that because the drug increases infections and reduces deaths - or is it because Omicron is a less serious but more infectious variant?

Also if you tell people "you're going to be taking a placebo" the likelihood of 1) getting people to sign up for it and 2) getting patients to comply will be low. (I mean, you can't give one group a placebo and the other group a fake placebo.) Why take a placebo if it's guaranteed to not work?

 

[C C]

A possible (in truth highly unlikely)

No way of knowing if you have been given placebo or not

For stuff like pain relief or sleeping tablets fine have a control group

Virus stuff affecting the immunity system a psychosomatic response to produce more antibodies very very questionable

The patient or subject can have expectations slash beliefs about the real drug that could exaggeratedly affect their reports or behavior, too, regardless of whether a placebo group is utilized. ("Behavior" including overconfidence leading to delays in seeking check-ups or medical attention -- albeit those actually working in slash conducting the studies could surely offer better reasons than I can conceive.)

But... when placebos are involved in a trial, if the researchers do not use data from a placebo group to assess that finer area and subtract some percentage of allowance for compromised results from those taking the real drug, then the whole matter is irrelevant. (I.e, placebos are superfluous for life-threatening health matters.)

Initially, I didn't consider the evaluation of a new drug to be that deeply thorough or painstaking a process in the comparisons of both groups. But I had to allow that I might be wrong.

 

[Sarkus]

Unfortunately you have the no-drug vs placebo-drug data taken at a different time in the pandemic (if you're referring to a drug/vaccine for COVID for example.) You therefore have data on no drug vs. Delta, and data on drug vs. Omicron.

You can test the drug on any specific sample you like, whether it is v Delta or v Omicron, so that issue is a red-herring, I'm afraid.
Sure, the "no drug v Placebo" would be while people are infected with Alpha, but that's the one at the time of the test, so that's what it is.
If a new variant comes out afterward, the clinical trials of no-drug or drug v the new variant would be identified by comparing groups who take the new drug and those who don't - i.e. you only ever sign up a test group. The unethical side, to me, is giving someone who agrees to be in the trial a placebo rather than the actual drug. The placebo effect might well be different for the new variant, true, but

What if the drug shows that serious outcomes are reduced (less death) but there are far more infections with moderate (i.e. symptoms that keep people home) outcomes? Is that because the drug increases infections and reduces deaths - or is it because Omicron is a less serious but more infectious variant?

I don't follow you, I'm afraid.
You can test it on groups with any specific variant you want. You always will have data on no-drug vs any variant - just by looking at what is happening to people with those variants who aren't in the trial. The issue here, to me at least, is the people in the trial not being given a potentially life-saving drug, and insisting on a placebo-control. It is that placebo-control that I would think could be done far earlier in the process, such that when new drugs arrive, they only need to test the effect on the trial group, not against a placebo as well.

Also if you tell people "you're going to be taking a placebo" the likelihood of 1) getting people to sign up for it and 2) getting patients to comply will be low. (I mean, you can't give one group a placebo and the other group a fake placebo.) Why take a placebo if it's guaranteed to not work?

That's why I specifically said that in this trial to establish the placebo effect the group would need to think they are potentially taking a genuine drug, in the same manner that they don't know if in current placebo-controlled trials they are getting a genuine drug or not. At no point would I tell any patient that they are "going to be taking a placebo". You tell all of them that they are testing a real drug. But it is in fact a placebo. Thus you test the placebo effect without anyone failing to benefit from an actual drug, and you don't get 9 people dying in the trial that potentially could have survived had they got the actual drug. Remember also that this test for the placebo would be in a test before any genuine drug is available for trial, so you're not failing to give people a genuine trial-drug.

 

[billvon]

You can test the drug on any specific sample you like, whether it is v Delta or v Omicron, so that issue is a red-herring, I'm afraid.

No you can't. Not if you are running the two tests at different times. There will be a different distribution of viruses. Right now it's primarily Delta; in a few months it will likely be Omicron. You can't "go back" to Delta.

(I mean, they don't intentionally infect people with COVID in vaccine trials - you know that, right?)

Sure, the "no drug v Placebo" would be while people are infected with Alpha, but that's the one at the time of the test, so that's what it is.

Correct. Thus making the test invalid. You can no longer compare the two samples to see if the drug is effective.

Double blind studies are the gold standard for several reasons. One is that all the participants, as much as possible, experience the same environment - the same strains of disease, the same stress from world events, the same mistakes from study providers. In fact, randomizing the distribution of placebo vs study medication is critical to that, so that (for example) all the placebo doesn't go to a poor neighborhood in Chicago that sees poorer outcomes to begin with.

That's why I specifically said that in this trial to establish the placebo effect the group would need to think they are potentially taking a genuine drug, in the same manner that they don't know if in current placebo-controlled trials they are getting a genuine drug or not. At no point would I tell any patient that they are "going to be taking a placebo".

You would have to. You can't actually lie to people in studies; that's unethical. You could tell them that they will get the study drug or a placebo, or you could tell them that they will get two different kinds of placebos, and which type will be unknown to them. But you can't lie to them.

Thus you test the placebo effect without anyone failing to benefit from an actual drug, and you don't get 9 people dying in the trial that potentially could have survived had they got the actual drug.

Right. But if the drug turns out to be deadly in combination with (say) polio vaccinations, your inclusion of the placebo might just SAVE those 9 people. Remember, at the point that they do these studies, they don't know if the drug does more harm than good. They SUSPECT it does more good based on animal studies - but animal studies have missed interactions many times.

 

[RainbowSingularity]

Do not discount the psychosomatic effect too readily.

a persons ability to alter their own physiology by mind control

quite a common subject among some religions & sports
but
the average person is the average victim & patient
& people have a certain length of time like fitness to which they can maintain a change in their physiology.

obesity might be a good statistical comparison to gauge from
which clearly shows psychosomatic effect is over ruled by addictive psychology

anxiety & shock have psychosomatic relationships
however
the effect on & in the brain can be the same as a physical event/virus/bacteria/bad diet/shock event

subconscious controls & default body controls
limbic control etc...

things like cytokine storms & co-morbidity over rule it

if you were administering in a group setting
where there was group interaction
psychosomatic effect would need to be gauged against placebo to factor base ranges
but none of which would be substantial against the damage caused by lack of effective medication.

if your suggesting some type of negative psychosomatic effect
you would need to provide some type of event & common value to trigger it as a group effect over & outside individual peoples life events etc.
(e.g who is the administering people & their behavior)

i doubt the hospitalizations are for minor issues & probably factor as a life saving event for a %

some cultures believe going to hospital is where you go to die
so they do not want to go to hospital
some would rather stay home lay down & die
there is still a considerable amount of paranoia & fear in modern western society towards peoples perception of going to hospital

No you can't. Not if you are running the two tests at different times. There will be a different distribution of viruses. Right now it's primarily Delta; in a few months it will likely be Omicron. You can't "go back" to Delta.

usa & private health user pays
defining experimental drugs as the norm via user pays affordability
muddys the waters considerably

question is
once sick
is the best possible solution provided
or denied

there lies the ethics & moral cliff face

did all the participants all get equal money medical cover for their hospitalizations & medical treatment ?
or was some of it lower quality via cost ?
THAT will be a question not wanted to be asked investigated or answered
because i strikes right at the very heart of user pays price class health care
while insurance is group class based

were all the patients hospitalized, hospitalized by he same people,
who knew if they were taking the drug or placebo ?
& what level of care were they given ?

 

[billvon]

question is
once sick
is the best possible solution provided
or denied

Generally doctors provide the best possible treatment. One problem arises when a patient wants a quack cure and the doctor cannot in good conscience use it, since he knows that the cure is ineffective and has drawbacks.

did all the participants all get equal money medical cover for their hospitalizations & medical treatment ?

Generally all study participants get any treatment associated with the study for free. Note that the study doctors are generally NOT the ones providing the care.

 

[sculptor]

Dr. Candace Pert states in her book Molecules of Emotion that "virtually all illness, if not psychosomatic in foundation, has a definite psychosomatic component."

 

[RainbowSingularity]

some side issues & questions

are people who look poorer &/or have lower class jobs
given less/lower quality health care ?

Generally doctors provide the best possible treatment. One problem arises when a patient wants a quack cure and the doctor cannot in good conscience use it, since he knows that the cure is ineffective and has drawbacks.

Generally all study participants get any treatment associated with the study for free. Note that the study doctors are generally NOT the ones providing the care.

bias ?
no co-pays = less profit ?
profit motive for lower quality of care ?


do medical staff get tips in the usa

my guess is no
why not ?

why are medical staff not tipped by the patient ?
how does that work morally in the system ?

 

[billvon]

no co-pays = less profit ?
profit motive for lower quality of care ?

Again, I don't know of any doctors who think "hey, these guys were in that study! I'm going to give them crappy care."

do medical staff get tips in the usa

my guess is no
why not ?

Because they are considered professionals, and not service industry workers, I imagine. I mean, you don't tip the guy who designed the airplane you flew on, do you?

 

[DaveC426913]

Remember, at the point that they do these studies, they don't know if the drug does more harm than good. They SUSPECT it does more good based on animal studies - but animal studies have missed interactions many times.

This.

 

[RainbowSingularity]

not service industry workers

nurses are service industry

why are they not tipped ?

the guy who designed the airplane you flew on

your clutching at straws
going soo far out on a limb you have changed the entire subject

people who service passengers are not the designers

they are called cabin crew(flight attendants/air crew)
& they dont seem to get tipped either & they are service workers

what is the difference between a poor quality nurse & a high quality waiter ?
surely the knowledge base can be considerably comparable & greater in either direction

why is one called a professional & the other is not ?
implicit classicism ?

your creating more questions than answering any

moving away from the subject
which i was mentioning
classicist service inside price classicism
or
wealthy
versus
coupons

the whole coupon thing is clearly a thing
& co-pay is an exploitation of the limits defined to take profit off the customer

tipping is the same
it is used to undermine & validate a lower trade position of the worker in exchange for magic bean promises

but which business owners are paying money for magic bean promises ?
none !
so why should the customer be forced to pay for them ?

i would have preferred a sane discussion

 

[Sarkus]

No you can't. Not if you are running the two tests at different times. There will be a different distribution of viruses. Right now it's primarily Delta; in a few months it will likely be Omicron. You can't "go back" to Delta.

Yes you can. You simply test for the variant you want before picking your sample group.

(I mean, they don't intentionally infect people with COVID in vaccine trials - you know that, right?)

Correct. Thus making the test invalid. You can no longer compare the two samples to see if the drug is effective.

Only "invalid" with regard the notion of placebo-controlled trials. When are you going to address the ethics of it, rather than the process?

Double blind studies are the gold standard for several reasons. One is that all the participants, as much as possible, experience the same environment - the same strains of disease, the same stress from world events, the same mistakes from study providers. In fact, randomizing the distribution of placebo vs study medication is critical to that, so that (for example) all the placebo doesn't go to a poor neighborhood in Chicago that sees poorer outcomes to begin with.

This is actually irrelevant, as it doesn't talk to the ethics of placebo-controlled trials, only to how they should run. I have no issues with how they should run, when they are run. Only in the ethics of whether the placebo-controlled trial is ethical or not. You're choosing to not really address that. Calling it the "gold standard", for example, doesn't in and of itself make it ethical. I'm sure there are "gold standards" in the use of capital punishment, after all.

You would have to.

No you wouldn't, just as you wouldn't tell people in a placebo-controlled trial that they are taking a placebo.

You can't actually lie to people in studies; that's unethical.

You wouldn't need to lie. You tell them that they are taking a drug that will help further their understanding of the virus etc. No lying needed. The fact that it's a sugar-pill or other pill with no active ingredient is not something they would need to know.

You could tell them that they will get the study drug or a placebo, or you could tell them that they will get two different kinds of placebos, and which type will be unknown to them. But you can't lie to them.

You could tell the entire study group that they are getting the study-drug, without telling them that the study-drug is a placebo. Again, this is not a placebo-controlled trial I'm talking about, but the study of a placebo drug itself. There is already a wealth of data of what happens when people don't receive a drug. But even here, if you want to run a placebo-controlled trial, comparing the placebo against drug X (also a placebo), do so. No lying needed: tell them they're going to either take a placebo or drug-X. They don't need to know drug-X has no active ingredient.

Right. But if the drug turns out to be deadly in combination with (say) polio vaccinations, your inclusion of the placebo might just SAVE those 9 people. Remember, at the point that they do these studies, they don't know if the drug does more harm than good. They SUSPECT it does more good based on animal studies - but animal studies have missed interactions many times.

Again, not actually relevant to the matter of ethics of placeb0-controlled trials. I'm aware that drugs need to be trialled, and that they can cause harm. Noone is suggesting that we don't run trials first. The issue is whether it is ethical to run placebo-controlled trials, when the placebo-effect can be done prior to any drug being available.

Look, if all you're going to do is explain the process of a placeb0-controlled trial, you're not really talking about the ethics of them. That's why this thread is in the "ethics" sub-forum, and not in the general science forum asking for the benefits of them. This is about ethics. Whether it is ethical to withhold the drug from members of the trial group simply to understand the placebo effect. Yes, people could die in the trial if things go wrong. That's the nature of testing on humans. That doesn't speak to the ethics of the placebo-controlled trial itself, though.

And let's move it away from the COVID situation, as that clearly seems to be causing a derail.

 

[Baldeee]

Sarkus, there are occasions when even the World Medical Association (WMA) deem placebo-controlled trials unethical, but I'll get to those in a sec.

First, the question here seems to be that 9 people died that maybe wouldn't have done if the trial had no placebo-control, and thus whether it is ethical.
Okay, the answer is to consider whether you have 500 people in the trial, all of whom get the trial drug, or you have 1,000 people in the trial, of which 50% get the trial drug.
In each case, 500 people get the drug.

What you don't get with the former, though, is precise detail of how the placebo group ended up.
All you could do is infer the benefit of the drug compared to those not in the trial at all (your "no-drug" group).
So since you aren't actually putting at risk/benefit any more people in the former than the latter with the trial drug, and the latter produces more accurate information about the placebo at the time, it is surely no less ethical to add in a placebo control than to not have one at all.
That's all there is to it.
If you're looking at the trial as being either 500 get the trial drug, or the 1,000 do, then it's a matter of ethics of trial size.
There's academic stuff on the web for that (e.g. https://pubmed.ncbi.nlm.nih.gov/15632258/) but it's beyond my ken.

All that said, there are times when placebo-controlled trials are deemed by the WMA as being unethical.
Notably when the placebo-control requires the group to be deprived of existing remedies/therapies.
But that would not be the case with the Covid drugs, as these are very much "add-ons" to existing, rather than replacement thereof.

Hope all that helps.