Europe votes for clinical trial transparency(alltrials.net)
alltrials.net
Europe votes for clinical trial transparency
http://www.alltrials.net/2014/europe-votes-for-clinical-trial-transparency/
45 comments
He sells shirts picturing a rubber ducky with "nutritionist" printed underneath: http://badscience2.spreadshirt.co.uk/sophisticated-visual-ga...
Congrats to ben goldacre and everyone else who worked on this!
Congrats to ben goldacre and everyone else who worked on this!
[deleted]
Getting all the information from all clinical trials will probably spur some great data mining efforts, on a much broader scale than what has been done so far. For example, a former colleague of mine used the correlation of published drug side effects between different drugs [1] to predict potential alternative therapeutic targets.
Getting all the data on drug efficacy, availability, correlate it with chemical structure, combine it with the information on other drugs could potentially help us a lot in predicting better working future drugs and the workings of existing drugs.
Also, transparency. No more picking out those trials that worked and conveniently forgetting about those that did not work.
[1] https://www.sciencemag.org/content/321/5886/263.abstract
Getting all the data on drug efficacy, availability, correlate it with chemical structure, combine it with the information on other drugs could potentially help us a lot in predicting better working future drugs and the workings of existing drugs.
Also, transparency. No more picking out those trials that worked and conveniently forgetting about those that did not work.
[1] https://www.sciencemag.org/content/321/5886/263.abstract
As far as I know, US laws require that the `x` number of trials demonstrate the effectiveness of the drug and failured dont need to be reported. But this does not make sense to me, and I welcome the European laws. In the US system, even if I have a coin biased badly against coming up heads, if I toss it enough number of times I will get `x` heads. The tosses cost money and that is then used to justify the patent system.
One of the oft repeated justification for the absurd levels of IP protection and patent extensions that pharma enjoys is the huge cost of trials. But if huge development costs are the reason for these protections to exist, guess what, these costs will continue to remain huge. Its just self perpetuating.
Patents are primarily a preemptive measure against a hypothetical scenario. The hypothesis is that unless market pressures are cordoned off, innovation will stop. It is a believable hypothesis but not a quantitative one, and this exactly where we need a quantitative one. How many years exactly does one need to subvert the market so that a satisfactory level of innovation is maintained ? Nobody knows. In these scenario what we need is a feedback system, and pretty much the only scalable and fair apparatus that we have for such feedback on economic affairs is the market.
So rather than subverting the market, market should be explicitly and actively involved to work out this trade-off. How exactly this is to be done needs to be worked out.
There could be a futures market on patents on drugs undergoing testing: competitors can promise to buy the patent to the (drug,usecase) pair at a particular price (even if its a dud) and if the owner decides not to sell the owner pay a particular compensation. Such measures will spread the risk. There should be mechanisms for a company to raise money for testing in lieu of rights over the product.
The initial period of validity of a patent should be short, like 3~6 years, following which the patent is on the market. Entities can bid to bring the patent to public domain. The owner(s) bids to retain it. Whoever wins gets the balance. Of course the "bring it to public domain" bidders will bid less because profitability is less when its in the public domain, but market decides who gets to own it. If the owner(s) think they can still extract lots of profit from the drug, bid high. We should stop handing out blank checks without a feedback loop, that is just bad design.
One of the oft repeated justification for the absurd levels of IP protection and patent extensions that pharma enjoys is the huge cost of trials. But if huge development costs are the reason for these protections to exist, guess what, these costs will continue to remain huge. Its just self perpetuating.
Patents are primarily a preemptive measure against a hypothetical scenario. The hypothesis is that unless market pressures are cordoned off, innovation will stop. It is a believable hypothesis but not a quantitative one, and this exactly where we need a quantitative one. How many years exactly does one need to subvert the market so that a satisfactory level of innovation is maintained ? Nobody knows. In these scenario what we need is a feedback system, and pretty much the only scalable and fair apparatus that we have for such feedback on economic affairs is the market.
So rather than subverting the market, market should be explicitly and actively involved to work out this trade-off. How exactly this is to be done needs to be worked out.
There could be a futures market on patents on drugs undergoing testing: competitors can promise to buy the patent to the (drug,usecase) pair at a particular price (even if its a dud) and if the owner decides not to sell the owner pay a particular compensation. Such measures will spread the risk. There should be mechanisms for a company to raise money for testing in lieu of rights over the product.
The initial period of validity of a patent should be short, like 3~6 years, following which the patent is on the market. Entities can bid to bring the patent to public domain. The owner(s) bids to retain it. Whoever wins gets the balance. Of course the "bring it to public domain" bidders will bid less because profitability is less when its in the public domain, but market decides who gets to own it. If the owner(s) think they can still extract lots of profit from the drug, bid high. We should stop handing out blank checks without a feedback loop, that is just bad design.
In the US you need two trials showing that a drug is effective, but you can have an unlimited number showing that it's not effective. Also it doesn't need to be shown to be effective against a disease, it can just be effective at reducing some number that correlates with a disease. And you don't need to show that it's effective in the longterm, only for up to 6 weeks - it could make the disease dramatically worse in the longterm, and that's fine even if the drug is meant for longterm use.
There are some rules trying to get all new trials registered, but the rules aren't followed at all and the FDA doesn't enforce them.
There are some rules trying to get all new trials registered, but the rules aren't followed at all and the FDA doesn't enforce them.
Wow, there is a long that is incorrect in your comment.
1. You are right that typically you need two registrational trials for approval and yes you can have many trials that show it doesn't work.
2. You are incorrect that you don't need to show it works against a disease. Sometimes you can show that you are impacting a biomarker (which I assume is what you mean by "some number"), but there must be evidence that changing the biomarker impacts the disease. Without that evidence you will not get approval.
3. You are incorrect you only need to show its effective for up to six weeks. If that were true, why would drug companies be running multi-year trials for cholesterol drugs? You typically need to show its effective for however long the drug is taken, but a follow-up period is also required.
1. You are right that typically you need two registrational trials for approval and yes you can have many trials that show it doesn't work.
2. You are incorrect that you don't need to show it works against a disease. Sometimes you can show that you are impacting a biomarker (which I assume is what you mean by "some number"), but there must be evidence that changing the biomarker impacts the disease. Without that evidence you will not get approval.
3. You are incorrect you only need to show its effective for up to six weeks. If that were true, why would drug companies be running multi-year trials for cholesterol drugs? You typically need to show its effective for however long the drug is taken, but a follow-up period is also required.
2) C.f. statins. There are any number of books that talk about this. Overdosed America comes to mind, but you'd be hard pressed to find any recent book about the pharma industry that doesn't talk about statins.
3) C.f. SSRIs, and Robert Whitaker's book anatomy of an epidemic.
3) C.f. SSRIs, and Robert Whitaker's book anatomy of an epidemic.
2) You are correct that new drugs can be approved by showing a lowering of LDL (biomarker), but that's only because the link between LDL lowering and cardiac risk reduction has already been demonstrated.
The best example I can give you right now are the drugs in development to treat Duchenne's muscular dystrophy. These drugs work by increasing the levels of a biomarker called dystrophin. The FDA recently came back and said "nope, not enough evidence that increasing dystrophin will improve patient's conditions, therefore we will not approve your drug".
As for the length of depression trials, it has been established that 6-week trials provide enough evidence to support an improvement in patients. [1]
Therefore, a 12-week trial is not necessary for all older patients; rather, the degree of improvement in the first 4 to 6 weeks identifies patients who are highly likely to benefit from continuing antidepressant treatment as well as those who very probably should have their treatment regimen altered at that point.
However, the depression drugs also run trials for long-term use: "Cymbalta is indicated for the treatment of major depressive disorder (MDD). The efficacy of Cymbalta was established in four short-term and one maintenance trial in adults [see Clinical Studies (14.1)]."
[1]http://www.ncbi.nlm.nih.gov/pubmed/16027559
The best example I can give you right now are the drugs in development to treat Duchenne's muscular dystrophy. These drugs work by increasing the levels of a biomarker called dystrophin. The FDA recently came back and said "nope, not enough evidence that increasing dystrophin will improve patient's conditions, therefore we will not approve your drug".
As for the length of depression trials, it has been established that 6-week trials provide enough evidence to support an improvement in patients. [1]
Therefore, a 12-week trial is not necessary for all older patients; rather, the degree of improvement in the first 4 to 6 weeks identifies patients who are highly likely to benefit from continuing antidepressant treatment as well as those who very probably should have their treatment regimen altered at that point.
However, the depression drugs also run trials for long-term use: "Cymbalta is indicated for the treatment of major depressive disorder (MDD). The efficacy of Cymbalta was established in four short-term and one maintenance trial in adults [see Clinical Studies (14.1)]."
[1]http://www.ncbi.nlm.nih.gov/pubmed/16027559
As far as I know, US laws require that the `x` number of trials demonstrate the effectiveness of the drug and failured dont need to be reported.
That is not correct. When you submit an NDA to the FDA, you need to include every piece of clinical trial data you've obtained so far. This includes trials that you've either ended early or failed to show any effect at all.
The FDA doesn't look kindly upon a company that hides any clinical trial data.
How many years exactly does one need to subvert the market so that a satisfactory level of innovation is maintained ?
We have some data on that, but we can't predict the future. I can't find the stat right now, but only about 1 in 3 drugs approved by the FDA actually produce an overall positive return.
That is not correct. When you submit an NDA to the FDA, you need to include every piece of clinical trial data you've obtained so far. This includes trials that you've either ended early or failed to show any effect at all.
The FDA doesn't look kindly upon a company that hides any clinical trial data.
How many years exactly does one need to subvert the market so that a satisfactory level of innovation is maintained ?
We have some data on that, but we can't predict the future. I can't find the stat right now, but only about 1 in 3 drugs approved by the FDA actually produce an overall positive return.
> even if I have a coin biased badly against coming up heads, if I toss it enough number of times I will get `x` heads.
I'm pretty sure a "trial" is a statistically significant study of many patients. So in this case, your analogy to the coin is flawed. A better analogy would be x groups of 10,000 coin flips, and to take the average of each group in x. Now, no such average would favor the less probably side of the coin.
I'm pretty sure a "trial" is a statistically significant study of many patients. So in this case, your analogy to the coin is flawed. A better analogy would be x groups of 10,000 coin flips, and to take the average of each group in x. Now, no such average would favor the less probably side of the coin.
No, grouping over many patients does not eliminate the loop hole at all. The 'coin' was my analogy for the event that a trial was deemed successful (according to some statistical test of hypothesis). If all that I need is to demonstrate is 2 trials that show statistically significant benefits, I can do that expenses permitting (unless the probability of benefit using my candidate drug is exactly 0). The key is that I am allowed unlimited trials where my candidate may not only show no statistically significant benefit but also show worse performance. If only the decision to accept my candidate is based on all the trials together is this hole plugged. My understanding is that FDA does not do this. 2 strikes and you are in, regardless of failure in the other trials.
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> • Require that a summary understandable to a lay person of what was found in the trial is published on the register.
Good luck with that. Explaining complex cellular mechanisms to a lay person without any scientific nor statistical background is a very difficult task. When you consider modern medicine, you need basic knowledge in genetics, biochemistry, biology, proteins, drug formulation, pharmacology, pharmadynamics, toxicity, clinical studies design, to have a proper understanding of what a study means. We're not talking about aspirin class of medicines anymore, and more and more drugs are now in the class of large molecules.
Good luck with that. Explaining complex cellular mechanisms to a lay person without any scientific nor statistical background is a very difficult task. When you consider modern medicine, you need basic knowledge in genetics, biochemistry, biology, proteins, drug formulation, pharmacology, pharmadynamics, toxicity, clinical studies design, to have a proper understanding of what a study means. We're not talking about aspirin class of medicines anymore, and more and more drugs are now in the class of large molecules.
>> • Require that a summary understandable to a lay person of what was found in the trial is published on the register.
>Good luck with that. Explaining complex cellular mechanisms to a lay person without any scientific nor statistical background is a very difficult task.
I don't think that the cellular mechanisms, or generally speaking the mode of action, are what has to be explained understandable to a lay person. What has to be explained is the result of the trial.
>Good luck with that. Explaining complex cellular mechanisms to a lay person without any scientific nor statistical background is a very difficult task.
I don't think that the cellular mechanisms, or generally speaking the mode of action, are what has to be explained understandable to a lay person. What has to be explained is the result of the trial.
Nowadays drugs work in tandem with biomarkers, so how do you explain what a EGFR mutant individual mean to a layman who has no knowledge about genetics and mutations ? You'll end up with "Drug A works better than B for EGFR wild type mutations but no different for other subsets". And? Is the layman supposed to understand what it means like that?
> Nowadays drugs work in tandem with biomarkers, so how do you explain what a EGFR mutant individual mean to a layman who has no knowledge about genetics and mutations ? You'll end up with "Drug A works better than B for EGFR wild type mutations but no different for other subsets". And? Is the layman supposed to understand what it means like that?
Of course the layman is not supposed to understand that, that is no explanation in layman's terms. You can make these sentences understandable by generalizing it: "We already knew before that the effect of these types of drugs is very specific to the specific genetics of a patient. Now in this trial we tried to find out what specific drug works for what specific genetic combination. The result is that Drug A works better than B for a combination that is called XY: Whether or not that applies to you can be found out by <test method>."
Of course the layman is not supposed to understand that, that is no explanation in layman's terms. You can make these sentences understandable by generalizing it: "We already knew before that the effect of these types of drugs is very specific to the specific genetics of a patient. Now in this trial we tried to find out what specific drug works for what specific genetic combination. The result is that Drug A works better than B for a combination that is called XY: Whether or not that applies to you can be found out by <test method>."
I see what you are aiming at, but the conclusion of clinical trials is almost never that simple. Drug A works better than B is a matter of statistical significance, of patient selection (history, previous treatments, genetics), and you can still register, nowadays, drugs versus placebo as comparators. So the issue of comparing two drugs together remain where no clinical trial to compare them in parallel exists. So you'll end up in these situations with : "Drug A works better than Placebo on X population" and "Drug B works better than Placebo on Y population", and the poor layman will be left on his own to understand how the X population is different from the Y one, and what to make of the results when it comes to comparing A and B.
In other words, it won't help laymen in the end.
At one point, if you really want to understand the clinical trial results, you need to go in details, and laymen won't be able to do that. So I'm not sure what they are trying to accomplish here.
Plus, you don't need that laymen language in the first place. Isn't that the job of journalists who cover scientific discoveries ? I'm afraid we hit another hurdle here, with the deplorable state of clinical trials results reporting in the general public by the media. That says a lot about what you can expect from laymen in terms of scientific comprehension.
In other words, it won't help laymen in the end.
At one point, if you really want to understand the clinical trial results, you need to go in details, and laymen won't be able to do that. So I'm not sure what they are trying to accomplish here.
Plus, you don't need that laymen language in the first place. Isn't that the job of journalists who cover scientific discoveries ? I'm afraid we hit another hurdle here, with the deplorable state of clinical trials results reporting in the general public by the media. That says a lot about what you can expect from laymen in terms of scientific comprehension.
> I see what you are aiming at, but the conclusion of clinical trials is almost never that simple.
Yes, that's the problem with study subjects as complex as humans :) My academic background is in educational science and things are even fuzzier there: there never is a simple treatment->result relation because the persons receiving treatment reflect on that treatment, they are an active part in it.
> In other words, it won't help laymen in the end.
I think I know what you're meaning, but that's the point where I disagree: In my opinion this is no either/or situation but rather a question of relative amount of insight that can be given to laymen: Currently they will usually understand 0% of the scientific abstract. If we assume that a laymen's version of that abstract loses 80% of the information but is 100% understandable, that would still be a win.
> Plus, you don't need that laymen language in the first place. Isn't that the job of journalists who cover scientific discoveries ?
Absolutely, as journalists are already used to do exactly that. In practice the result will probably be exactly that: the institution will have science journalists who will produce these laymen's abstracts.
Yes, that's the problem with study subjects as complex as humans :) My academic background is in educational science and things are even fuzzier there: there never is a simple treatment->result relation because the persons receiving treatment reflect on that treatment, they are an active part in it.
> In other words, it won't help laymen in the end.
I think I know what you're meaning, but that's the point where I disagree: In my opinion this is no either/or situation but rather a question of relative amount of insight that can be given to laymen: Currently they will usually understand 0% of the scientific abstract. If we assume that a laymen's version of that abstract loses 80% of the information but is 100% understandable, that would still be a win.
> Plus, you don't need that laymen language in the first place. Isn't that the job of journalists who cover scientific discoveries ?
Absolutely, as journalists are already used to do exactly that. In practice the result will probably be exactly that: the institution will have science journalists who will produce these laymen's abstracts.
It might not be possible in every case, but it sounds like a laudable goal to me.
Also, what do they tell people who take part in trials - I'd be pretty annoyed if I took part in a trial and someone told me "we can't tell you because with your humble CS education you wouldn't understand it".
Also, what do they tell people who take part in trials - I'd be pretty annoyed if I took part in a trial and someone told me "we can't tell you because with your humble CS education you wouldn't understand it".
People who take part in trials usually dont care about the science, they take part in it because all the other treatments failed and they are willing to try something new. That's their main incentive, at least for life threatening diseases.
Not really true. Phase 1 (safety and tolerance) trials will be done by any old berk. And I've entered trials because yay, science, even if I have a disease that's treatable by an existing clunky method.
Oncology phase 1 trials are made on cancer patients only, so no, your statement is not 100% correct.
Plus, phase I trials are really limited in size, so they are meaningless versus the total population of people who go on clinical trials for phase 2 and 3 - and these are patients always.
Plus, phase I trials are really limited in size, so they are meaningless versus the total population of people who go on clinical trials for phase 2 and 3 - and these are patients always.
But you see, this is why its ever more important to have public data available - so that people can educate themselves on these things, if they want to.
Its sort of like in the bad ol' days of computing - you used to have to know all kinds of arcane things just to be able to get some numbers crunched. Nowadays, if you want, you can look at the source for your OS .. this is the same effect that needs to happen in the pharmaceutical industry, and I for one look forward to the reduction in sheer Power over peoples Lives that the pharma mega-industry has had, as people start to realize that there is a lot of smoke and mirrors in what they're being told 'is a solution to their problems .. for $99/month' ..
Its sort of like in the bad ol' days of computing - you used to have to know all kinds of arcane things just to be able to get some numbers crunched. Nowadays, if you want, you can look at the source for your OS .. this is the same effect that needs to happen in the pharmaceutical industry, and I for one look forward to the reduction in sheer Power over peoples Lives that the pharma mega-industry has had, as people start to realize that there is a lot of smoke and mirrors in what they're being told 'is a solution to their problems .. for $99/month' ..
Well, a trial is not about the molecular mechanisms of a drug. It is about checking whether a drug works and whether it is better than existing drugs. So statistics.
Still hard, obviously, and plenty of space for semantic whitewashing.
Still hard, obviously, and plenty of space for semantic whitewashing.
A trial usually tries to justify a mechanism of action. That's the least you try to do when you spend hundred of USD millions in a Phase 2 or 3 trial. And anyway even if a drug works better than another, it's almost never a black and white result, because drug safety profile usualy differ. You'll end p with a one pager result most laymen won't be able to grasp, no matter how you want to simplify things.
Albert Einstein said something along the lines of if you can't explain a concept to your grandmother, you don't know it well enough. I'm sure he didn't have a molecular biologist with a Ph.D. kind of grandmother in mind.
You can explain everything if you have the patience and will to break it down to pieces for others to understand.
You can explain everything if you have the patience and will to break it down to pieces for others to understand.
Yeah I'm sure his grandmother had no problem understanding the general theory of relativity. Do you have other end all discussions quotes to share?
> Yeah I'm sure his grandmother had no problem understanding the general theory of relativity.
Here[1], try and see if you can understand it. I'm sure you can, I'm sure your grandmother can too. Also if you have any specific questions about pharmacology, molecular biology or anything related feel free to ask, I might be able to come with a reasonably simple answer.
[1] https://www.youtube.com/watch?v=YgpD4XZP0uM
Here[1], try and see if you can understand it. I'm sure you can, I'm sure your grandmother can too. Also if you have any specific questions about pharmacology, molecular biology or anything related feel free to ask, I might be able to come with a reasonably simple answer.
[1] https://www.youtube.com/watch?v=YgpD4XZP0uM
They'll have prepared material already explaining the purpose of the trial for the purpose of obtaining informed consent. The text for the result will have to be written up but even that will be mostly boilerplate.
This is great news - no more pharmaceutical profit projects getting pushed to the forefront, only to discover a few years later that the adverse affects were buried in 'company proprietary confidental' reports .. makes it safer to live in Europe!
In the US, this is already present, to some extent, with FDAAA 801 [1], which requires that all clinical trials be registered before they start. Missing things like required publication and the "human-readable" digest, but the absence of data can be factored in by the FDA when considering approval -- that is, studies that terminate without reaching a finding can be considered weak indicators of problems, and in the long run, potentially point to organizations or individuals who might be suppressing negative results.
Even required publication is no cure for this; a result saying "we inadvertently broke the blind" or "the protocol was poorly implemented" is perfectly possible even in good faith.
[1] http://www.clinicaltrials.gov/ct2/manage-recs/fdaaa
Even required publication is no cure for this; a result saying "we inadvertently broke the blind" or "the protocol was poorly implemented" is perfectly possible even in good faith.
[1] http://www.clinicaltrials.gov/ct2/manage-recs/fdaaa
For God's sake, another article that conflates Europe and the EU! Lazy, lazy journalism.
Another popular decision by our MEPS just in advance of the EU parliament elections this summer.
Next comes mom and then apple pie.
Next comes mom and then apple pie.
The EP is actually quite good at producing the right decisions, especially when the public remember that it exists and lobby them over this issue. Unfortunately it's the weakest of the legislating institutions (Parliament/Commission/Council).
Yes. I'd like to have EU institutions which look more like "normal" democratic systems, and greater power for the EU parliament. But it's still a lot better since the Lisbon treaty.
Another excellent decision made by the MEPs that the general public will simply not give a shit about. Your cynicism is too high. Votes for "tax the right", "throw out the immigrants", "abandon the EU" are popularism. Good science and technology votes stand by themselves.
Maybe your right but to my mind there's been a suspiciously high level of superficially praiseworthy pronouncements emanating from Strasbourg just lately.
Given the limited powers of the parliament do they carry any more weight than politicians' pre-election promises?
I don't know where you live 3 billboards on my way to work are now taken up with advertisements on behalf of our local MEP. She had been all but invisible previously.
As I said in a comment lately she has recently been on the radio here claiming credit for another measure that promises much but has been criticised for being easily sidestepped.
Given the limited powers of the parliament do they carry any more weight than politicians' pre-election promises?
I don't know where you live 3 billboards on my way to work are now taken up with advertisements on behalf of our local MEP. She had been all but invisible previously.
As I said in a comment lately she has recently been on the radio here claiming credit for another measure that promises much but has been criticised for being easily sidestepped.
As others here have alluded to the powerlessness of the MEPs allows them the freedom to do the right thing.
Well, yes, elected politicians doing things their constituents want so that they'll get re-elected is surely the point of the system.
http://en.wikipedia.org/wiki/Bad_Pharma
http://en.wikipedia.org/wiki/Bad_Science_%28book%29
I wonder if you can get "I am a Nutritionist!" T-shirts?
[Edit: Thanks for pointing out the T-Shirt pretty much does exist].