h2g2 The Hitchhiker's Guide to the Galaxy: Earth Edition

Hi

A couple of links you might find useful when writing about the way that journal editors look at drug company-sponsored clinical trials:

http://bmj.bmjjournals.com/cgi/content/full/326/7400/1167

http://news.bbc.co.uk/1/hi/health/3640488.stm

Of course, as a writer of drug-company sponsored papers, if the journals get their way, I'll be out of a job. Probably for the best in the grand scheme of things, but not something for me to look forward to!

Hey Danny,

just read those articles you linked here.
Amazing, I never thought that this type of "fraud" (a bit harsh, I know) would occur in scientific research.
One would think, with the fact that a company may just simply funding a trial (so no own research personnel would be involved, e.g use of CRO) that there wouldn't be a biased result. Yet there seems to be one.
Of course the CRO would want to maintain a good relationship with its client and getting "good" results would make that easier, wouldn't it? But I guess that doesn't matter for the personnel of the CRO who are actually doing the work (Data Reviewers, Statisticians, Medical Writer...), they couldn't care less, because they have no "real" relationship with the client. Only the CEO does (and some other members of the management team perhaps).

I find it very disturbing. It just goes to show that sometimes economics are more important that human lives.

BTW: I had a look at the online registration of trials, an initiative by PhRMA. A bit of a turn-off, since it is incomplete. For about 90% of the registration are studies by American companies. What about the rest of the world, guys?!

Hmm... I could write for hours on this subject, but I'll try not to (particularly as I'm supposed to be earning a living committing scientific fraud at this precise moment )

The fraud (a little harsh, yes!) occurs at two points.

1. The design of the trial, which is done by the pharmaceutical companies in consultation with medics and the CRO. This is often (not always) designed to maximise the perceived benefits of the drug in question.

2. The publication of data, which is 'spin', not fraud, in that you will not get away with publishing anything that is actually false. But, yes, publication of data does tend to focus on positive results at the expense of negative results.

However, looking at it from the other side, it can take up to $1 billion dollars to develop a single new drug. As long as that money is spent by pharmaceutical companies, they have to make the money back, as well as sufficient profit to develop more drugs (and, yes, keep the shareholders happy...) To make a profit, they have to sell drugs. To sell drugs,they have to advertise and market their product. Nobody (in any field) markets their product by harping on about its bad points.

The majority of drugs are in competition with similar products. If company A says:

Drug X has good points A, B and C; while Drug Y has bad points D, E and F

And company B says:

Drug Y has good points G, H and I, while Drug X has bad points J, K and L

...than you can argue that the downside of both drugs will eventually make it into the public domain. Even if company A want to cover up bad point K, you can guarantee that as soon as company B get the slightest incling of it they will advertise the fact far and wide.

Personally, I think we'd all be a lot better off if drug development were a nationalised industry, but what government can afford $1 billion dollars per new drug? Therefore, as long as drug development remains a commercial operation, there will be pressure to use conventional marketing techniques, including a lot of 'spinning' of data.

A registry of data is a great thing, but how many doctors would have time to actually look at it? All they will see is, as it is now, publications of those data sponsored by drug companies. It will just mean that Companies A and B have more information about their competitors weaknesses than before. I can't see the overall situation changing that much, as long as commercial pressure to sell drugs remains.

Right - going now (not actually committing fraud at the moment; merely writing a literature review! )

I gues at this point in our society it can't be helped that companies want to maximise their profit. Especially with the generic drugs on the market. People do tend to forget that for every drug that is released on the market, 10 don't make it that far (maybe more, just guestimating here)

Nationalising of the industry won't do any good, I think. Communism only works in theory
For now, I'm a strong believer of the free market and healthy competion. Although sometimes it turns a bit unhealthy, e.g. GSK and the antidepressant.

What I do find sad is the spinning of data. I can agree that in study design they want to maximise the effect of the drug (if there is no effect, they can't maximise it, so that's not a big bias). But the spinning...Companies should publish failed trials. Of course, that way the competion knows what they don't have to try and can better invest in something else. But I think it levels out, every company will know what the competition has done and failed in.
The registration is a joke and I don't think it will do any good. Besides, there are already good site where people can look for studies which they want to join as study subjects. That's about the same as a registration database.

"Companies should publish failed trials."

Fair enough - but you try getting a peer reviewed journal to accept a paper based on a trial that didn't work. It's hard enough getting them to accept trials that did work!

"Of course, that way the competion knows what they don't have to try and can better invest in something else."

It's not so much for that reason that companies don't want to publish failed trials. It's because as soon as such a result appeared, competitors would go all out to highlight that fact and, in a _reductio ad absurdum_ type way, insist to anyone who'll listen that the drug simply doesn't work.

Because, people see four trials of a drug that works, but they're company sponsored, so no-one believes them... As soon as they see trial 5, in which the drug didn't work as well as in the others, it's very tempting (and human) to leap to the conclusion that it doesn't really work, especially when the competitors are forcing Trial 5 down everyone's throat. Spin works both ways, which is why I don't get too hot under the collar about it!

The GSK-Seroxat/Paxil matter is an interesting one, in that full details (including the suicide data) should legally have been made available to regulatory authorities (FDA etc.) before the drug was licensed. Either the company didn't do that (and I'm not saying they did or didn't, in case the libel lawyers are watching ), or the regulators didn't spot the risk. Even so, 'covering up' an increased risk of suicide is something (I'd like to believe) that could only happen in an extreme case. Usually, when people talk about not publishing negative data, it's to the effect that the drug causes slightly more nausea than a competitor, or was only slightly more effective than placebo in a given trial, something of that nature - minor things that a competitor could jump on and make a lot of noise about.

"Usually, when people talk about not publishing negative data, it's to the effect that the drug causes slightly more nausea than a competitor, or was only slightly more effective than placebo in a given trial, something of that nature - minor things that a competitor could jump on and make a lot of noise about."

Doesn't that work both ways? Like: "you make lot's of noise about my drug, I'm gonna make even more noise about yours".
Then again, that way more energy (and money) would be going into marketing and advertising the negative of other drugs instead of the positive of one's own drug. And that is an awful lot of wasting (what with Kyoto and all...)

"Fair enough - but you try getting a peer reviewed journal to accept a paper based on a trial that didn't work. It's hard enough getting them to accept trials that did work!"

That's not the idea of peer review, is it? Isn't it the job of your peers to check if the methods that were used were legitimate? They shouldn't care whether the trial worked or not. Sometimes a negative result can say more than a positive (e.g. HIV *sorry*)

Here's the propsal as it was first formulated (also check out the links at the bottom of the article for discussion on the topic):

http://content.nejm.org/cgi/content/full/NEJMe048225

Most doctors, you're right, won't have the time, skills or inclination to sift through un-analysed trial data. But independent statisticians and journal editors will - ideally it will make the idea of peer review more transparent.

It's an interesting and contentious issue, which I haven't really swotted up enough on. Follow the link and see what more learned minds than I have to say about it

Matt

'Doesn't that work both ways? Like: "you make lot's of noise about my drug, I'm gonna make even more noise about yours".'

Well, yes, you'd have thought so. But the people in drug marketing are just that - marketing people - and they've been trained that you mustn't let the slightest negative thing about your product slip out, while all the time looking for anything remotely negative about the competitor that you can capitalise on.

"Isn't it the job of your peers to check if the methods that were used were legitimate? They shouldn't care whether the trial worked or not."

The reviewers probably don't. But editors do. Like everyone else, journal editors have a commercial interest - ie, they need to publish data that are interesting, newsworthy and scientifically valid so that people will subscribe to their journal, advertise in their journal etc. "New drug works" is news. "Clinical trial fails" is not news, therefore a trial that fails to meet its primary endpoint is very difficult to publish. You can argue that this is an issue throughout science publishing - it's very difficult to publish 'negative data' (ie, experiments that don't work), when it might actually be useful to some people to see what has been tried and didn't work (sounds like a definition of my thesis )

"Most doctors, you're right, won't have the time, skills or inclination to sift through un-analysed trial data. But independent statisticians and journal editors will - ideally it will make the idea of peer review more transparent."

But who's going to pay for it? Most journals couldn't afford anyone to do that on a full time basis, and I think peer reviewers might balk at the idea of having to trawl through the entire trial data set (tens of thousands of pages for even a moderately sized Phase III study) while reviewing a publication. While it might be handy for regulatory agencies who want to check up on something, I can imagine that the only people who would use the registry regularly would be drug companies, who probably could afford to employ a statistician or reviewer to spend their days looking through competitor data for angles of attack.

Or maybe I've been in the business too long I've become a little cynical

I know I said that companies should publish (or let publicly known) which trials failed, but I'm gonna reconsider.
I think if this were compulsory, it can have some negative side effects

1. Companies will have an extra incentive for making trials work. Otherwise the competion will have a weapon in the marketing battle. So, this in mind, I think the bias that sneaks up during trial design development will become even bigger. It becomes more important than before to NOT fail a trial. So instead of eradicating bias, it will induce it.

2. Extra budget will be needed to fight in the marketing battle. Hence, drugs will become more expensive. With the generic drugs remaining cheep (no investment is needed for research and marketing, because that has already been done by other companies, who first developed the original drug), that price increase will not be favorable for the selling of non-generic drugs. That's your basic supply-and-demand.