Should randomised trials be the only type of evidence accepted for rolling out drug treatments?
If so, then two researchers wrote in the Lancet this week that that we face a problem:
The evidence we have might not be the evidence we need, and the evidence that we need may never become available.
They are writing in response to the publication of a trial of a new combination drug treatment for stomach cancer that seems to extend people’s lives by nearly 3 months.
According to these guys, there’s probably lots of effective combinations of current cheap drug treatments to treat cancer, but we’re never going to get the evidence to prove it.
The new trial must have been crazy expensive: It consisted of patients from 122 different institutions in 24 counties on 4 continents and, as the editorialists point out, it would never have been paid for had it not promised huge returns for the pharmaceutical company that funded the trial, Roche.
This raises a sticky issue. Drug companies like Roche produce treatments that save lives. But they don’t do so because they save lives. Rather, they produce the drugs because they can make the company money.
So what happens when these two motivations come apart — when drugs that could save lives don’t make drug companies money? That’s the problem that the Lancet editorialists are referring to.
If we presuppose that only randomised trials produce evidence of sufficient quality to support decisions about the allocation of scarce resources, there is a problem. There is a lot of evidence on the effects of adding expensive new drugs to conventional therapies, but little evidence for when older, less expensive interventions are combined.
And boy are these drugs expensive. In the same comment piece, the authors calculated that the cost of each year of life gained by this new treatment, is about $100,000 AUD ($85,000 USD).
The authors of the study argue that this should be rolled out as a “new standard option” in the treatment of gastric cancer — and that’s not surprising given that the manufacturer of the drug not only funded the trial, but was involved in the data analysis and editing of the report.
So how are we supposed to get evidence about cheap drugs that will help millions of people but not make money for drug companies?
I don’t know. The authors mention the model in physics where large projects that don’t have obvious practical benefits are funded by governments and research institutions. And they seem to imply that there might be a way of not relying solely on randomised trials — but they don’t say what that is.
Whatever the way forward, it seems crazy that in the mean time, we can only get evidence about drugs which, for the majority of people around the world, are prohibitively expensive when there’s almost certainly some great cheap alternatives right under our noses.
Munro, A., & Niblock, P. (2010). Cancer research in the global village The Lancet DOI: 10.1016/S0140-6736(10)61022-7
Bang, Y., Van Cutsem, E., Feyereislova, A., Chung, H., Shen, L., Sawaki, A., Lordick, F., Ohtsu, A., Omuro, Y., & Satoh, T. (2010). Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial The Lancet DOI: 10.1016/S0140-6736(10)61121-X
Drug companies like Roche produce treatments that save lives. But they don’t do so because they save lives. Rather, they produce the drugs because they can make the company money.
This is a direct result of adopting a belief system that says the desire to make money will solve all of humanity’s problems. That is, the Friedman-esque idea that an unregulated free market will always self-correct, always police itself, and always deliver the highest possible results for society.
We are so blindly devoted to that belief that we fail to see the obvious problems it causes. Markets can get hijacked by those who can control them (megacorporations), the mandate for corporations to produce the products as cheaply as possible and sell them for the highest possible price, price-fixing, and human corruption all can pervert markets. Add in the fact that a lot of money can be made off human suffering, war, and disasters, and you have a recipe for a market controlled by huge megacorporations that is based on exploiting the suffering of humanity.
It wasn’t supposed to work out that way. It was supposed to provide us a gleaming future where everybody had good jobs, and access to the best hearlth care and technological conveniences science could offer. At least that’s what the Friedman people promised us.
If you want someone to find an economical way to help others, you don’t simultaneously charge them with a mandate to make as much money as possible with any proposed solutions they may deliver. Yet that’s exactly the double-sided agenda we give Big Pharma.
Gee, how many masters’ degrees in economics does it take to figure that out?
More than most of our top economic advisors to the President have, apparently.
I’m not sure what I said that is a direct result of that belief system… But otherwise I agree. There are lots of things that markets will not deliver, and cheap effective drugs is one of them.
“It was supposed to provide us a gleaming future where everybody had good jobs, and access to the best hearlth care and technological conveniences science could offer.”
You’re telling me this doesn’t describe the US?? At least before the last economic downturn when unemployment began to skyrocket…
I’m not sure where you have been getting your history, but the battle between democracy/capitalism and collectivism/socialism/statism pretty much dominated the twentieth century. And I thought it was pretty obvious that democracy/capitalism came out on top by a wide margin. Whereever those two concepts have been put into practice, people have flourished. On the opposite end of the spectrum, you get things like East Berlin, North Korea, or Iran.
Additionally, the unregulated free market you describe just doesn’t exist in reality. You attempt to knock down a huge straw man, but then fail to do that very well. Under the system you describe, how on earth does a place like Wal-Mart exist? Because it’s obviously their goal to charge the absolute highest prices on the planet for everything they sell…
Last point – have you ever met anyone in the medical or pharma community? They’re people, just like you and me. If they had a drug that would cure cancer, but wouldn’t make their company a single penny, absolutely they would bring it to market in a heartbeat. Anyone would except, perhaps, straw men of your own invention.
Can anyone name one treatment or drug that is effective at treating, well, anything that hasn’t been made publicly available because it wouldn’t make a drug company money? Start with concrete examples first, drop the straw men, and maybe I’ll start to listen to your argument.
Hi Tom.
I’m not arguing for socialism (not here anyway!) but a few things you say are not quite right.
Of course it doesn’t. The US has one of the worst health care systems in the western world. Hopefully it will start to improve now, but it has nothing on most of Europe, Australia or Cuba. Millions of people do not have access to, what you describe as, the best health care technological conveniences.
The market that wallmart operates in is very different to the international pharmaceutical market. It’s not really even worth outlining the many differences since there’s almost nothing they have in common. As you say, “free markets” rarely exist and while the one that wallmart operates in is, in some ways, a free market, the pharma market is not.
Yeah, I deal with pharma everyday. Of course they are mostly great. But no company will pursue a strategy that will not make them money. Developing drugs costs a hell of a lot of money and it’s a simple fact that they will not develop a drug that is unlikely to make them any money.
What this post was about was not about pharma not bringing drugs to market because they’re not profitable, but not developing them in the first place. So it’s a bit hard to point to drugs that haven’t been developed. However, the issue raised in this post is as close as it gets: no pharmaceutical company is going to fund trials of combinations of existing drugs because they can’t make a profit on that. It just doesn’t happen. Instead, there’s lots of trials of combination therapies of new, expensive drugs. This is not just the opinion of this blogger or the above commenter, but the opinion of the expert writing in the Lancet.
There are, however, plenty of cases of drugs that were initially not distributed because of lack of profit possibilities. The first antidepressants in the 50s is one case. Not until the definition of depression changed so that the drug had a bigger market, did pharma decide to market them. Aids drugs is another classic case. There are drugs that essentially let people with HIV live out a full, normal life. And they could be marketed to people in Africa if it weren’t for the requirement for pharma to make as much profit as possible.
Michael,
I appreciate your reply. I was directing my comments about free markets more to yogi-one, but you bring up some interesting points that I respectfully disagree with. Let me make my criticism a bit more clear.
Let’s assume your premise for a moment. If there are indeed treatments out there waiting to be tested if someone would only spend the money, would there not be scores of medical journal articles, op-ed pieces, or TV interviews given by doctors or researchers bemoaning this fact? The Lancet is making the point that we don’t know what we don’t know, and we don’t know it because pharma is out for profit. I would argue that if this were indeed true, we’d know a little more about what we don’t know and we’d be having a different conversation.
Big pharma makes money. They have to because, as you’ve stated, it costs a lot of money to develop and get drugs approved. But there are other options when it comes to something like, say, the AIDS drugs you mentioned.
For starters, I disagree with your premise that drug companies didn’t market those drugs to Africa because they are ‘required’ to make as much money as possible. Obviously, if something like that is going to put the future of the company at risk they’re not going to do it (why would/should they?), but the rest of the world in the case of Africa wasn’t much help. International aid organizations or other governments could have funded the drugs on a massive scale, but they didn’t. Hell, African countries could have funded the drugs but they didn’t. And as it is almost exclusively a sexually transmitted disease, Africans could have stopped it, but for the most part they didn’t. And this is an argument after the fact, but how did Africa as a whole get into their predicament in the first place? Because of the lack of democracy and capitalism.
The trials you and the Lancet argue may be needed can be done, but its incorrect to blame pharmaceutical companies for not doing them. Governments fund all sorts of research (ask someone working on Global Warming, for example) so if there was political will, there would be a way. Don’t make drug companies the target. They are for-profit businesses, and that’s a good thing. I would argue that medical treatments would not be as advanced as they are right now were it not for companies that make a profit.
On the other side of that coin, I disagree with your assertion that pharmaceutical companies don’t have an altruistic bone in their collective bodies. They are mainly led by doctors, all of whom (I would assume) have taken the hippocratic oath and would jump at the chance to cure X and be able to say their company did it. And I have no doubt they’d come up with a way to monetize it, somehow.
Finally, you said that you weren’t arguing for socialism, but once you start demonizing companies for making a profit, you’re well down the path. Someone once said that communism (which I’ll equate to socialism here for our purposes) is real good at making everyone equal….equally poor. Same thing applies to medicine – I continue to read horror stories from the UK and Canada about their socialized medical programs.
The UK is beginning to free theirs up as a result. If you want decisions about how to treat an illness or fund a drug trial taken out of the hands of for-profit companies, then you almost by necessity put them in the hands of politicians. Politicians, in the US at least, have given us things like the Post Office and the Department of Motor Vehicles. I don’t want them in charge of my medical treatment.
I sympathize with your sentiment. It would be nice if doctors weren’t worried about money. World peace and an end to oppression and slavery and prostitution would be nice, too. But we’re talking about reality here, not utopia, which means there are going to be trade-offs and hard choices. Going back to my earlier point, at a public policy level striving for utopia gets us things like North Korea and, I’m afraid, Cuba.
To summarize – you may have a point (I won’t yet concede that you do), but if you do it’s certainly not the fault of the pharmaceutical companies, nor is it their job to correct it.
Hi Tom,
I’m not sure what there is to disagree with regarding the claim about what Pharma chooses to pursue. There are announcements made everyday about what pharma is deciding to invest in and what they aren’t and nobody tries to hide the fact that these decisions are made based on where the most profit to be had is.
Saying that, is not demonising pharma. (There are other reasons to demonise pharma. See: avandia and vioxx.) It’s merely pointing out that if we rely on two things: randomised trials, and pharma funding them, then we won’t find out about treatments that are not profitable.
And one example of this kind of treatment was given in the Lancet article: combination therapies made up of cheap, existing drugs.
I agree with you that we wouldn’t have lots of the great treatments that we have today, were it not for pharma. But I think you also seem to agree with me that if we want things developed that aren’t profitable, then we need to either find new ways to develop them, or new ways to fund their development.
You say that you’re worried about the decisions that government would make if they were developing drugs. But that is not warranted since all the decisions about the implementation, the sale — everything — of drugs is made by the government (the FDA in the US, the TGA in Australia etc.)
So I’m not so much arguing for revolution, as for people to come up with ways of making sure that we get treatments that won’t necessarily make money for pharma.
Michael,
I think we have found common ground, but it also seems that ground is a far cry from the rather paranoid comment from yogi-one, which you said you mostly agreed with.
And unless I’m mistaken, the FDA in the US only certifies the efficacy and safety of a drug that a company wishes to sell. I’m not an expert, but if they already control “everything” about drugs then that is news to me.
One final thing – something I haven’t articulated well in the last two comments – if there is a demand for something, anything, then it will be profitable for someone. With the exception of the air we breathe, I can’t think of another commodity that someone isn’t making a profit on somewhere. You and The Lancet is say there’s a possibility that there may be combinations of existing, low cost drugs to treat some sort of ailment. My point is, were there science-based medical evidence pointing to a treatment of that type, someone (maybe not a drug company) would have found a way to test it, package it, and make a profit from it. People make a profit selling homeopathy and acupuncture for God’s sake, and there is a booming market in generic drugs.
So I think we still have a little disagreement, but you’re right that there are many points upon which to agree.
Hi Tom — glad we agree on a lot. But there’s one fundamental thing I think you’re quite mistaken about.
You have a faith in markets that not even Adam Smith would have had.
That’s just not true. Let’s just take a made up example to simplify matters. Let’s suppose that lots of people would like product X. Now, imagine that there are 1million people in the US willing to pay $5 for an X. But now suppose that developing X into something you can package and sell costs 5 million dollars. It is therefore not profitable for anyone to try to take X to market.
This is exactly the case with combination therapies of existing drugs. You cannot take a therapy to market unless you have the evidence showing a benefit. But gathering that evidence might cost half a billion dollars. For existing drugs for which there are many generics, the company that produces that evidence is not going to make their money back.
You could imagine lots of markets for which there is demand, but it would be crazy to try to bring the product to market because the costs will not be recouped through profits. I don’t know, I’m just making things up but imagine moon rocks. I’m sure there’s a market for rocks taken from the moon but nobody will pay enough for them to cover the costs of them being collected. Luckily, moon rocks are not important. But good combinations of current drugs could save a lot of lives — they just won’t be able to make a profit for the company that proves that.
Just one further rejoinder: This fact is so well accepted that its the basis of allowing patents on new products. The problem is that combinations of old products cannot be patented — and so nothing can ensure profits will be made.
Michael – you’re correct that I do have faith in the free market system, although I couldn’t quantify whether I have more or less than Adam Smith.
One obvious thing you may be overlooking is that demand for medical X (services, drugs, etc.) is fairly inelastic. Gasoline is another example of this – it is a product which is necessary (right now) for many things in our daily lives. As a result, we’re willing to pay a relatively high price per gallon for it before we change our behavior to consume less of it. If combinations of existing drugs were shown to cure/alleviate/supress X better than anything else on the market, then those 1 million people would almost certainly pay $6 (or more) instead of $5.
Smarter and more experienced people than I would have to do a cost/benefit analysis, of course, but again given the fact that any number of bogus and completely ineffective treatments are currently sold for a profit I feel certain that someone would be willing to try. Which brings up another benefit of free markets – people are always willing to try new things…and fail spectacularly. These are almost always smaller or upstart companies – a big, established company has too much to lose.
And again – all of this assumes that the unknown unknowns described in the Lancet article actually exist, something I have trouble believing.
As for patents – Bayer still markets and sells branded aspirin even though the patent for it has long since expired and cheaper generic brands flood the market (and I’m not even sure who held the original patent). You do have a point that the start-up costs for an endeavor like the one we are debating could be high, but in a free market that values and encourages entrepreneurs I do have faith that someone would take the plunge. And if not, or if there is the political will to speed matters up a bit, government can always incentivize the behaviour through tax breaks or straight subsidies.
Tom — asprin is not a counterexample. To market asprin, you do not have to undertake an enormous randomised controlled trial. Of course there is a market in generic drugs. But the whole reason why you can have patents on new drugs is so that people can recoup the costs required to develope them. The problem is that similar costs are involved with combining old drugs, but no patents are possible. There’s really nothing to disagree with here — not even the drug companies would disagree with this. In fact, I bet that if they were engaged in this debate, they would argue for expansion of the patent system.
Michael – fully stipulated. My point in bringing up aspirin was to say only that companies will produce and market – and people will pay higher prices for – a branded product functionally identical to a cheaper generic version. By extension, they should be willing to pay higher prices for any potential new combinations of drugs like the ones we’re discussing (and in the hypothetical example you used, would cost $5). Looking back at my comment now I wasn’t being very clear.
Another thought occurs to me, however, a question for which I don’t know the answer. What is the primary driver of cost in drug R&D? If it is the trials themselves then I think we both have valid points and are debating around the margins. If the primary driver of costs is the research and design of the drug itself and not the trials, then costs in the model we are discussing should be significantly lower as the drugs we’re talking about have already been discovered. As I said, I don’t know the answer, and as I’ve been out of my depth for the better part of our discussion I won’t speculate further.
Yeah — that’s right. The issue here is about the trials. The question of which is more expensive depends a lot on the drug.
The fact that people will pay more for the combination drugs if forced to is irrelevant because there are other companies that can undercut the company that payed for the trials. I can wait for you to do the trial, and then sell the drug at cut-price myself.
A couple of companies have taken cheap generics (topiramate -newly off patent in US + fenfluramine and doxepin – an old tricyclic antidepressant) and are trying to get FDA approval as diet drugs. The first was turned down for psychiatric side effects (thoughts of suicide and the like – when Topamax was DTC marketed here, the manufacturer had to take out 4 magazine pages, 2 for the ad and 2 for the warnings), second hasn’t made it before the committee yet. Another diet drug candidate was a novel molecule, also turned down (IIRC for psychiatric side effects). Obviously there’s a massive market for such products here, perhaps they should be limited to those with BMIs over a particular number and require a monthly visit to the prescribing physician and/or certain tests before refills are given.