"Don't stop the statin!"

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Herainestold
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Re: "Don't stop the statin!"

Post by Herainestold » Tue Jan 07, 2020 12:18 am

GeenDienst wrote:
Mon Jan 06, 2020 9:40 pm
I've told you, Herainestold, bring something better than your handwavy conspiracy bollocks or f.ck the f.ck off.

I've had a very interesting discussion with Pucksoppet about how non-publication of trials isn't going to influence the clinical database on statins. You've brought nothing.
Their bad beaviour isnt affecting the out come you say. Okay. Its still bad behaviour (hiding trials). It may affect future outcomes.

We still need a better system where the participants are not motivated by money

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Gentleman Jim
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Re: "Don't stop the statin!"

Post by Gentleman Jim » Tue Jan 07, 2020 8:36 am

Herainestold wrote:
Tue Jan 07, 2020 12:18 am
GeenDienst wrote:
Mon Jan 06, 2020 9:40 pm
I've told you, Herainestold, bring something better than your handwavy conspiracy bollocks or f.ck the f.ck off.

I've had a very interesting discussion with Pucksoppet about how non-publication of trials isn't going to influence the clinical database on statins. You've brought nothing.
Their bad beaviour isnt affecting the out come you say. Okay. Its still bad behaviour (hiding trials). It may affect future outcomes.

We still need a better system where the participants are not motivated by money
Let's employ all those unicorns that will out of work when Brexit is the success we have been told it will be

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GeenDienst
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Re: "Don't stop the statin!"

Post by GeenDienst » Tue Jan 07, 2020 10:37 am

The conversation with Pucksoppet made me think of the situation in diabetes, which may be moving the whole business of clinical trials forward. Hence this overlong ramble about that.

Brief story, back in 2007 or so a bloke called Nissen did a meta-analysis on a diabetes drug, rosiglitazone, and found an increase in mortality. Everybody jumped on that in a shock horror way, including Goldacre, as it happens, even though none of these trials were powered for outcomes, and a lot of them were only six weeks long, and IIRC none were longer than a couple of years. Garbage in, garbage out. Nobody much believes this any more, even though rosiglitazone is dead, as is its stable mate, pioglitazone, pretty much, even though pioglitazone improved (secondary) CV outcomes in a randomised cardiovascular outcomes trial (CVOT), and probably would have hit its primary outcome if that had been specified better (see here).

Anyway, that led to people thinking, hang on, we really don’t do anything to guarantee the cardiovascular (CV) safety of these drugs before they hit the market. So, the FDA came up with a cunning plan. Very briefly:

* All Phase II and Phase III trialsa must have design that makes them suitable for inclusion in a meta-analysis for effects on hard CV outcomes. This is always a composite outcome, usually “three-point major adverse cardiovascular outcomes (3P-MACE)”, typically death from a CV cause OR myocardial infarction [heart attack] OR stroke. Sometimes 4P-MACE also includes hospitalisation for unstable angina or heart failure or something, if something else is of special interest.

*If the 2-sided upper 95% confidence interval (CI) for MACE against placebo is below a 1.3, a CVOT is generally not required, i.e. the drug is considered safe (enough). I don't think this has happened, because there aren't enough bodies in the meta-analyses to get that sort of precision. Even if it did, the company would need to do a CVOT, as all the competition has, as per below.

*If the upper 95%CI is between 1.3 and 1.8, a CVOT is needed to show that an upper 95%CI of less than 1.3. This trial can happen while the drug is on the market.

*If your meta-analysis had the upper 95%CI more than 1.8, then tough tit, you need to do more trialling to get it below 1.8 before you can submit your application to the FDA, or no go.

This has had major implications for trials and data:

a) There have been a lot of new drugs coming out in diabetes recently. In practice, they always hit the 1.3-1.8 range, so all need a postmarketing CVOT. This means a shitload of CVOTs, and subsequent meta-analysing (Christmas every day for NEJM, Lancet and the leading diabetes journals). All of the many trials here are powered for outcomes, at least for non-inferiority (see below).

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b) Remember, all the Phase II trials go into that FDA-mandated meta-analysis. The FDA routinely puts the application documents online (see this for one of them, that shows all the trials). Nowhere to hide there.

c) The trials are usually designed as safety studies. The statistical plan usually demonstrates non-inferiority vs. placebo first, followed by a hierarchy of effect on, say, primary outcome (usually 3P-MACE), then MI, then CHD death, then all-cause death…whatever…and as soon as one of these is not significant, analysis for superiority stops. Any nominally significant effect on any other endpoint further down is only viewed as exploratory (New Engl J Med doesn’t even allow p values to be displayed for these).

d) If superiority for a given outcome or component of an outcome is demonstrated, the drug will get an indication for that.

e) This has led to muttering from senior triallists that it’s a something of a lottery – what ends up as significant, and only these end up in the label as a therapeutic indication, depends on the order in which the endpoints are analysed.

This has certainly increased the transparency of CV (and other) safety evaluation of these drugs by provision of loads of data, though clearly there is enough commercial interest in the diabetes field to justify CVOTs. Doesn't address other things, like how representative these trials are to Mrs Scrote in Barnsley, who has 17 different comorbid ailments and who wouldn't get within 7 miles of inclusion in a trial, but there you go, that's what observational studies are for, or "real world data" as we all call it now.


aQuick, basic and undoubtedly incomplete overview of trial phases for anybody new to this, reasonably tyoical of diabetes field, at least…
Phase I – first administration to humans, typically a dozen or two healthy volunteers, wide range of doses given, measure things like pharmacokinetics (PK; how long it stays in circulation), maybe first idea of pharmacodynamics (what it’s supposed to do) and safety/tolerability (look for unexpected side effects, don’t usually find any much). Modelling of PK is useful to set dosing for Phase II...
Phase II – first demonstration of efficacy, and initial tolerability/safety. Several. of these, usually. Size varies, maybe fifty to a couple of hundred patients with the disease in question, randomised for something like 6 weeks to 6 months. Some dose ranging [use trial(s) to select one or two doses for the next step], good initial idea of tolerability and safety.
Phase III – the biggie, that leads to a label, usually only one. Hundreds of patients (maybe thousands), longer duration (up to a few years, often until a pre-specified number of endpoints are measured, enough to drive the statistics). Formal statistical demonstration of efficacy, much better idea of tolerability and safety. Can address a surrogate endpoint (e.g. blood pressure), or hard clinical outcomes (e.g. MACE). Hard outcomes are adjudicated, i.e. a committee blinded to treatment reviews records and decides if Patient 003456y/2b really did have a heart attack or not - reduces bias and increases accuracy.
Phase IV – a trial conducted while the drug is being marketed. Often observational, may be randomised.

PS: Pucksoppet - I'm still going to get seven shades of agreement out of you - outside, now.
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murmur
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Re: "Don't stop the statin!"

Post by murmur » Tue Jan 07, 2020 11:19 am

Herainestold wrote:
Mon Jan 06, 2020 9:15 pm
murmur wrote:
Mon Jan 06, 2020 11:23 am
Herainestold wrote:
Mon Jan 06, 2020 2:56 am
Pharma is making billions from statins.
Commercial enterprises make money! Shock! Horror! Probe!

In other news Pope's religious affiliations confirmed and toilet habits of bears revealed.

Do you actually have a point in posting that?

PS Boiron makes billions from sugar pills and slightly impure water.
All those billions are a huge incentive for Pharma to cheat, hide negative trials, ignore side effects et cetera.
Imagine those billions used to discover new treatments for marginalized POC patients instead of lifestyle enhancements for wealthy white males.

What would a post capitalist Pharma regime look like? Universities doing basic research and publicly funded, not profit based, entities choosing which treatments to test and designing transparent trials where both negative and positive results are published. How do we get there from here?
OK, so start a new thread about the problematic nature of a capitalist pharmaceutical industry (BTW no-one here is denying that there are problems inherent in our current model, but we are kinda stuck with an overall capitalist economic model for the time being) and we could try having a serious discussion about that - not just vague handy wavy hints at conspiracies and denigration of teh ebil monies while having a fit of the vapours.
It's so much more attractive inside the moral kiosk

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Re: "Don't stop the statin!"

Post by Hunter » Fri Jan 17, 2020 7:21 am

I would like someone/some organization to remove all current commitments (minus his family commitments) from Ben Goldacre so that he could finish his book: Do Statins Work?: The Battle for Perfect Evidence-Based Medicine.
Then I would have the information I can trust.

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Re: "Don't stop the statin!"

Post by Hunter » Fri Jan 17, 2020 8:51 am

GeenDienst wrote:
Mon Jan 06, 2020 12:20 pm

And there's the other point that Goldacre never seemed to make - even in the hugely unlikely event that a Phase III CV outcomes trial is unpublished (and we would need to see examples of this, you can't hide an investigator-led, three-to-five year trial in hundreds or thousands of patients very easily), the regulators still get to see the data from those trials.

I think Goldacre pointed out that the regulators could be influenced by the revolving door nature of the industry.

GeenDienst, I respect your depth of knowledge on this subject.

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GeenDienst
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Re: "Don't stop the statin!"

Post by GeenDienst » Sat Jan 18, 2020 12:53 am

Hunter wrote:
Fri Jan 17, 2020 8:51 am
GeenDienst, I respect your depth of knowledge on this subject.
Well, that's more than I do. And your point is entirely valid, but perhaps a different one.
Just tell 'em I'm broke and don't come round here no more.

tom p
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Re: "Don't stop the statin!"

Post by tom p » Wed Jan 22, 2020 4:00 pm

Hunter wrote:
Fri Jan 17, 2020 8:51 am
GeenDienst wrote:
Mon Jan 06, 2020 12:20 pm

And there's the other point that Goldacre never seemed to make - even in the hugely unlikely event that a Phase III CV outcomes trial is unpublished (and we would need to see examples of this, you can't hide an investigator-led, three-to-five year trial in hundreds or thousands of patients very easily), the regulators still get to see the data from those trials.

I think Goldacre pointed out that the regulators could be influenced by the revolving door nature of the industry.

GeenDienst, I respect your depth of knowledge on this subject.
Goldacre cast unwarranted aspersions and was fundamentally wrong in his claims.
That's because he was, like some kind of anti-vax tw.t would, just parrotting sh.t from the US instead of actually bothering to do any proper research.
The salaries paid by the EMA are a matter of public record. It would be trivially easy to find out how they compare to equivalent posts in industry and realise that it is, in fact, individuals in industry who have an incentive to please the EMA in the vain hope of getting a job and not vice versa.

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Chris Preston
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Re: "Don't stop the statin!"

Post by Chris Preston » Thu Jan 23, 2020 8:32 am

Herainestold wrote:
Mon Jan 06, 2020 9:15 pm

All those billions are a huge incentive for Pharma to cheat, hide negative trials, ignore side effects et cetera.
In fact they are not. At least not for the big players. These companies typically have more leads than they have money to get them registered. At multiple points they have to select winners and dump losers. If they have a product that they know has poor efficacy or unacceptable side effects, there is no point in spending the millions on a Phase III trial only to have these turn up and doom the product. Better to dump the product and put the money into something that has a lower risk of failure.

The incentive may be higher for small players who have fewer or only one potential product.

Negative trials are indeed hidden all the time, but these will be trials for indications that don't work and are not going to be registered. There is no point in telling your competitors where the rabbit holes are. Better to let them spend their own money exploring the rabbit holes, while you do something else.

Once a product has been released, then the incentive for companies to try and cover over any subsequent problems increases. However, in analysing the response of companies to potential problems, you have to realise that many papers raising safety questions about chemicals of all sorts using animal models are often underpowered, have inadequate dose ranges and involve a fair bit of hand waving. It is not unnatural for a company to go on the defensive in such circumstances. There is not always fire where people claim they see smoke.

The fact that the number of scandals is small is an indication that cheating, etc. in the regulatory process is less common than some people would like us to believe.
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GeenDienst
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Re: "Don't stop the statin!"

Post by GeenDienst » Thu Jan 23, 2020 11:47 am

And, a small reminder of a couple of key points...

1. Statins are generic here, even the potent ones.

2. At least thirty properly powered CV outcomes trials in the Cholesterol Trialists Treatment Collaboration, using primary endpoints that are (or a close to) the recognised gold-standard primary endpoints for CV outcomes trials today (X-point MACE).

3. Consistent outcomes from these trials (and no, there aren't any hidden outcomes trials).

I challenge anyone to find a treatment with a bigger, better understood evidence base, except maybe insulin. And that only has three outcomes trials I can think of offhand (DCCT, DEVOTE, ORIGIN).

So let's simply not bother with the ebul-farmer-cuntspirasee bollocks. It's not relevant to this.
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Re: "Don't stop the statin!"

Post by dyqik » Thu Jan 23, 2020 11:02 pm

Chris Preston wrote:
Thu Jan 23, 2020 8:32 am
Negative trials are indeed hidden all the time, but these will be trials for indications that don't work and are not going to be registered. There is no point in telling your competitors where the rabbit holes are. Better to let them spend their own money exploring the rabbit holes, while you do something else.
Only from the POV of the companies. From the point of view of the governments that fund their research (directly or by buying the drugs for patients), this is a massive waste of public resources.

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Chris Preston
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Re: "Don't stop the statin!"

Post by Chris Preston » Thu Jan 23, 2020 11:20 pm

dyqik wrote:
Thu Jan 23, 2020 11:02 pm
Chris Preston wrote:
Thu Jan 23, 2020 8:32 am
Negative trials are indeed hidden all the time, but these will be trials for indications that don't work and are not going to be registered. There is no point in telling your competitors where the rabbit holes are. Better to let them spend their own money exploring the rabbit holes, while you do something else.
Only from the POV of the companies. From the point of view of the governments that fund their research (directly or by buying the drugs for patients), this is a massive waste of public resources.
It wouldn't happen where governments directly fund, because all that work has to be reported.

Yes it is a waste of resources, although it does not directly tie to the costs of drugs. Rarely does the price charged for a new drug reflect the exact cost of making the drug. The prices are more often set by what the market will bear. Expensive to produce drugs in an already competitive market place will not go forward unless manufacturing changes can get the price down. Even then, they will be marketed with slim margins to keep the price similar to competitors. Cheap to manufacture drugs in a non-competitive market will be priced high to maximise returns. I should point out that for pharmaceuticals, this is largely a north American phenomenon. In some other jurisdictions, governments interfere in the marketplace to reduce the costs of drugs.

Indirectly it will have an impact, as the extra costs will come out of company profits and reduce the funds available for developing the next product.
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Re: "Don't stop the statin!"

Post by tom p » Fri Jan 24, 2020 2:08 pm

Chris Preston wrote:
Thu Jan 23, 2020 11:20 pm
dyqik wrote:
Thu Jan 23, 2020 11:02 pm
Chris Preston wrote:
Thu Jan 23, 2020 8:32 am
Negative trials are indeed hidden all the time, but these will be trials for indications that don't work and are not going to be registered. There is no point in telling your competitors where the rabbit holes are. Better to let them spend their own money exploring the rabbit holes, while you do something else.
Only from the POV of the companies. From the point of view of the governments that fund their research (directly or by buying the drugs for patients), this is a massive waste of public resources.
It wouldn't happen where governments directly fund, because all that work has to be reported.

Yes it is a waste of resources, although it does not directly tie to the costs of drugs. Rarely does the price charged for a new drug reflect the exact cost of making the drug. The prices are more often set by what the market will bear. Expensive to produce drugs in an already competitive market place will not go forward unless manufacturing changes can get the price down. Even then, they will be marketed with slim margins to keep the price similar to competitors. Cheap to manufacture drugs in a non-competitive market will be priced high to maximise returns. I should point out that for pharmaceuticals, this is largely a north American phenomenon. In some other jurisdictions, governments interfere in the marketplace to reduce the costs of drugs.

Indirectly it will have an impact, as the extra costs will come out of company profits and reduce the funds available for developing the next product.
On one level, the original quote "Negative trials are indeed hidden all the time, but these will be trials for indications that don't work and are not going to be registered. There is no point in telling your competitors where the rabbit holes are. Better to let them spend their own money exploring the rabbit holes, while you do something else." is both true and somewhat reasonable. On another level, when it comes to medicines, it's both neither always true nor acceptable.
Humans volunteer to be in trials. We do so in hope that it might help us, but also in hope that it might help someone else in the future. We are being experimented on for the profit of a big corporation and we should only be experimented on if there's a need to. If as a species we already know that drug x doesn't work, then we shouldn't be exposed to either the risk of side effects or wasting what might be our one shot at a cure for our cancer.

If a clinical trial in humans is conducted anywhere in the EEA or the US, then it will be registered and all the pharmaceutical industry will be aware that it's being conducted. If the same substance doesn't go on to the next phase of clinical trials, then all the pharma industry know it doesn't work for whatever it was being tested for. I used to work in pharma publishing and know about the very expensive journals & databases available to the industry all about this stuff. It's a part of the industry where £20k for 12 issues/annum of a journal isn't a big deal because if one article every 10 years saves you 1 day of drug development (getting it approved quicker), then it's value for money, and then some. If it saves you a month of unnecessary clinical trials, then it's value for money.

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Re: "Don't stop the statin!"

Post by Gentleman Jim » Fri Jan 24, 2020 2:26 pm

tom p wrote:
Fri Jan 24, 2020 2:08 pm
I used to work in pharma publishing and know about the very expensive journals & databases available to the industry all about this stuff. It's a part of the industry where £20k for 12 issues/annum of a journal isn't a big deal because if one article every 10 years saves you 1 day of drug development (getting it approved quicker), then it's value for money, and then some. If it saves you a month of unnecessary clinical trials, then it's value for money.
One of the things I dearly miss from working in pharma, is the free access to what seemed to be, evry science journal ever published, plus tons in other subjects, too.
And just think, I was helping to pay tom p's wages too :lol:

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Re: "Don't stop the statin!"

Post by Cardinal Fang » Fri Jan 24, 2020 5:16 pm

tom p wrote:
Fri Jan 24, 2020 2:08 pm
If a clinical trial in humans is conducted anywhere in the EEA or the US, then it will be registered and all the pharmaceutical industry will be aware that it's being conducted. If the same substance doesn't go on to the next phase of clinical trials, then all the pharma industry know it doesn't work for whatever it was being tested for.
In an ideal world that would be true. In reality it isn't. It takes a lot of time and effort to keep track of every trial registration (assuming it gets made, which it doesn't always), and then to follow up a while later about whether results from those trials have been published AND that the outcomes of the study haven't been switched (which if they have can be just as instructive). There are very few bodies following up on these things at all (the CeBM is one). I doubt drug companies are prepared to cough up for researchers to spend all day every day trawling through all the journals ever published to match papers up with registered trials.

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tom p
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Re: "Don't stop the statin!"

Post by tom p » Fri Jan 24, 2020 11:25 pm

I believe I mentioned about databases and journals that do that sort of thing. And the companies all pay a lot of money, but less than 1 uk-based low-level FTE, for access to them.
I respect you, fang, but you are dead wrong about this.
Plus, I'm a regulator. We have the access to this sort of thing and my employers just defeated 2 a..eh.le drugs companies in court and we will soon be able to make way more stuff publically available. But we always had access. Goldacre's last few years of writing felt like one long whinge about quacks not having access to the data that regulators do, cos those front-line quacks with their 10 minute slots have the time to sift through stuff. Silly arse.

ETA also, you are saying that people are routinely breaking the law by not registering trials. EOSTFU*. Seriously. We actually do know what's going on. Also, an MAH has to include all the global trials ongoing or completed in the between the last DLP and the current one in their PSUSA.
If the meaning of that last sentence was not immediately blindingly obvious without need to look up the acronyms, then you don't have the knowledge to judge whether your statement is accurate or not.

*please give me the evidence, and I will have people prosecuted

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Chris Preston
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Re: "Don't stop the statin!"

Post by Chris Preston » Fri Jan 24, 2020 11:36 pm

tom p wrote:
Fri Jan 24, 2020 2:08 pm
On one level, the original quote "Negative trials are indeed hidden all the time, but these will be trials for indications that don't work and are not going to be registered. There is no point in telling your competitors where the rabbit holes are. Better to let them spend their own money exploring the rabbit holes, while you do something else." is both true and somewhat reasonable. On another level, when it comes to medicines, it's both neither always true nor acceptable.
Humans volunteer to be in trials. We do so in hope that it might help us, but also in hope that it might help someone else in the future. We are being experimented on for the profit of a big corporation and we should only be experimented on if there's a need to. If as a species we already know that drug x doesn't work, then we shouldn't be exposed to either the risk of side effects or wasting what might be our one shot at a cure for our cancer.

If a clinical trial in humans is conducted anywhere in the EEA or the US, then it will be registered and all the pharmaceutical industry will be aware that it's being conducted. If the same substance doesn't go on to the next phase of clinical trials, then all the pharma industry know it doesn't work for whatever it was being tested for. I used to work in pharma publishing and know about the very expensive journals & databases available to the industry all about this stuff. It's a part of the industry where £20k for 12 issues/annum of a journal isn't a big deal because if one article every 10 years saves you 1 day of drug development (getting it approved quicker), then it's value for money, and then some. If it saves you a month of unnecessary clinical trials, then it's value for money.
I was thinking of animal studies rather than human trials when I wrote that.
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