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Ethical concerns in medical trials

I just read this article on the treatment of medical volunteers, written by doctor and bioethicist Carl Ellliott.

As a statistician who has done a small amount of consulting for pharmaceutical companies, I have a slightly different perspective. As a doctor, Elliott focuses on individual patients, whereas, as a statistician, I’ve been trained to focus on the goal of accurately estimate treatment effects.

I’ll go through Elliott’s article and give my reactions.

Elliott:

In Miami, investigative reporters for Bloomberg Markets magazine discovered that a contract research organisation called SFBC International was testing drugs on undocumented immigrants in a rundown motel; since that report, the motel has been demolished for fire and safety violations. . . . SFBC had recently been named one of the best small businesses in America by Forbes magazine. The Holiday Inn testing facility was the largest in North America, and had been operating for nearly ten years before inspectors noticed there was anything wrong.

Wow! Of all the small companies in the country, they picked a criminal enterprise! I mean, sure, Forbes magazine is a joke, but still, I’d think that, all other things being equal, they’d prefer to restrict their endorsements to legal businesses. In 2003, SFBC wasn’t just on the list; it was ranked #3 in the nation!

Here’s a little research project for you: Go back to the Forbes list of 200 best small companies, follow them up, and find out how many have been breaking the law, giving people tuberculosis, etc.

Elliott:

Over the past 20 years or so, without much fanfare, clinical research has undergone a remarkable free-market conversion. Until the early 1990s, most pharmaceutical research on human subjects was conducted by physicians in universities and teaching hospitals. (The FDA, which must approve drugs before they can be marketed, doesn’t conduct clinical trials itself.) However, pharmaceutical companies have been in search of cheaper, more efficient venues and today about 70 per cent of clinical trials take place in the private sector, often in the offices of private physicians or at dedicated sites. . . . The research that many of us used to imagine as a humanitarian enterprise, carried out by selfless scientists and funded by Pink Ribbon campaigns and ‘Race for the Cure’ marathons, is actually a thoroughly Taylorised corporate system, outsourced and streamlined for maximum efficiency.

Efficiency can be a good thing, no? But the system has changed:

What does clinical research look like when everyone is in it for the money? For a start, it looks a lot less like science. ‘I do not do original research; I do contract research,’ says a private physician-researcher in Medical Research for Hire. A contract researcher does not come up with original ideas, or design research protocols, or analyse research results, or write them up for scientific publications. All of this is done by the pharmaceutical company or its hired specialists. What a contract researcher does is recruit subjects, monitor their clinical care and sign off on the paperwork. Not a lot of original work is done, and in some cases, not much work at all.

This is all ok with me in principle. What’s the role of the front-line doctor in this sort of study, anyway? It’s not at all clear to me that this doctor should be doing research; maybe he or she should be monitoring and taking care of the patients in the study. This might not be carried out well in reality, but in principle I don’t see the need for the on-site doctors to feel that they’re doing original research. If the original research is being done at the lab, why not use on-site doctors who can focus on clinical care of the patients.

But are these doctors actually taking care of anybody? Or are they just being paid for their “M.D.” credentials? It doesn’t look good:

The industry term for these near absent physicians is ‘phantom investigators’. Usually they will ‘come in on a daily basis, on most days, and they’ll sign off on all the things they need to sign off on, see any patients they need to see, and they’re gone’ . . .The researchers are usually on-site for no more than an hour or two a day. Contract researchers may not do much intellectual work, but this doesn’t mean they are not well paid. A part-time contract researcher conducting four or five clinical trials a year can earn an average of $300,000 in extra income. . . . Even an ordinary office visit will be paid at twice the usual rate if the visit is part of a research study. . . .

Contract researchers may find that their sponsors do not welcome bad news about the trials, especially if the drug appears unsafe. Reporting that subjects have experienced a ‘serious adverse event’ (industry-speak for the worst side effects) may mean losing the contract.

Sounds like bribery to me. The story, as I take it, is that these doctors are being paid big bucks to keep their mouths shut, to keep people in the study no matter what, and to downplay adverse events. An independent doctor, not dependent on the drug company for the money, might very well advise a patient to take a different treatment if problems arise.

Here, I wonder if statisticians are part of the problem? We go on and on about the threats to validity of causal inference if patients drop out of a study or don’t take the assigned treatment, and this puts enormous pressure on researchers not to “cheat” and to keep everybody in. Perhaps recent statistical research on causal inference from broken experiments is not merely helpful but necessary for ethical experimentation.

Now on to the patients. Elliott writes:

Ready to recruit patients are sick people who can easily be persuaded to enrol in clinical trials, often because they are so poor that they have no better alternative. . . . For years the demand for research subjects has been growing, driven not least by the sheer number of clinical trials being conducted in the desperate search for new blockbuster drugs. Nobody really knows how many trials the industry is currently conducting, but a WHO official estimates that 20,000 are initiated each year. They are getting larger and more complex, partly to satisfy safety regulations, but also because many of the drugs being tested are so similar to drugs already on the market: if a new drug is only incrementally better than a control drug or placebo, demonstrating a statistical difference requires many more research subjects.

Aahhhh, more statistics! Perhaps “equivalency tests” are enough: are 1% differences in effectiveness really important?

Between 1995 and 2006, the highest annual increases in the number of active clinical researchers occurred in Russia, Argentina, India, Poland, China and Brazil. Many of these places have established a foothold in the industry as ‘rescue countries’: drug companies go there when they need data quickly – when their trials in the West have failed to show the drug is effective, for example . . .

Hey–this doesn’t seem quite right!

Financial incentives present a different ethical problem for a Phase I trial, the purpose of which is to determine if a drug is safe. Most Phase I trials are done on healthy subjects. Until the mid-1970s, this usually meant prisoners; today the trials are done mainly on the poor, who sign up for the money. . . . The issue of payment has always worried regulators and ethicists, who are concerned that excessive fees will tempt impoverished subjects to take risks with their health. Nevertheless, the amount of money offered to subjects has, over the years, gradually crept up. . . . The most lucrative studies are longer trials testing the safety of new drugs, with lots of in-patient time and plenty of unpleasant medical procedures. These sometimes pay subjects upwards of $6000.

Paying people seems fair to me, but this part doesn’t seem right:

Guinea pigging may have become a job, but it does not carry many benefits. Research subjects do not have the right to workers’ compensation, health insurance or a minimum wage. Trial sites are not regulated in the same way as workplaces. If subjects are harmed by the drugs they take, they have no right to compensation, and they may well have to pay their own medical expenses. According to a survey published in the New England Journal of Medicine, only 16 per cent of the policies issued by academic health centres in the US offer free care to research subjects injured in trials.

There’s also this, which doesn’t make sense to me:

The move to poorer countries intensifies the ethical problem created by a market-based trial system. . . . by enrolling in trials they can get drugs that they could not otherwise afford – never mind that the drugs are experimental, or may be placebos.

Is this really correct? I thought that, nowadays, you have to compare a new treatment to the best existing alternative, not to placebo. So, if you do get a placebo, it’s not like you’re worse off than if you weren’t in the study at all. But maybe I’m missing something here?

Elliott’s conclusion:

By turning clinical research over to the market we have created a system in which private physician-investigators can make far more money persuading their patients to enrol in research studies than by simply treating their illnesses; in which patients sign up to test new drugs, either because they need the money or because they have no way to pay for ordinary healthcare; in which investigators are financially punished for telling companies that their drugs are risky or dangerous; and in which even ethical oversight has become a revenue-generating mechanism.

I’m interested in how statistical methods are causing problems here and also how they can be part of the solution.

6 Comments

  1. Is this really correct? I thought that, nowadays, you have to compare a new treatment to the best existing alternative, not to placebo. So, if you do get a placebo, it's not like you're worse off than if you weren't in the study at all. But maybe I'm missing something here?

    No, its not correct. Mostly, placebos are still used, especially given that many of the "growth areas" are places where there is no effective treatment.

    Funnily enough, regulators often demand that the size of the placebo group be reduced if there is a treatment which seems effective. The problem is that this then increases placebo effects (if you have an 80% chance of getting real drugs, then even if you get placebo you'll likely think it real and improve anyway).

  2. perceval says:

    Ben Goldacre, a psychiatrist and epidemiologist, has very similar concerns He's either working or has finished a book on Big Pharma. I tweeted your post and tagged him – I hope he pops over.

  3. A. Zarkov says:

    SFBC did not give anyone tuberculosis. If you read the Bloomberg article you will see that the SFBC Montreal testing center accidently put two people in the same room where one had active tuberculosis. SFBC was certainly negligent, but that's a far cry from what sounds like something the Japanese and the Germans did during WWII. The person with the active case came from Haiti, a place with an astronomical rate of tuberculosis infection. One is left to wonder how this guy got into a clinical trail in such a condition. One can also wonder how he got into Canada in the first place. Was he an illegal alien? SFBC certainly sounds like an awful company that should get put out of business. But let's be critical of the national governments that don't seem to want to control our borders.

  4. Larry says:

    "I thought that, nowadays, you have to compare a new treatment to the best existing alternative, not to placebo."

    No, I think it's really correct, for most drugs you need only be better than the placebo. Hence, the proliferation of "me-too" drugs.

    I think Marcia Angell has written a lot about this stuff.

    http://www.nybooks.com/contributors/marcia-angell

  5. I like how you both publicized and improved Mr. Elliot's flawed article.

  6. Rodney Sparapani says:

    Whether you compare a new drug to placebo depends on the current "standard of care". In cardiology, that used to mean that comparisons with placebos were OK. However, more recently, the FDA has decided than comparisons with competitors, if available, is necessary. So, it depends on the condition and what the FDA considers "standard care".