Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients (16 page)

That’s an extreme case. But even at best, volunteers come from less well-off groups in society, and this creates a situation where the drugs taken by all of us are tested – to be blunt – on the poor. In the US, this means people without medical insurance, and that raises another interesting issue: the Declaration of Helsinki, the ethics code which frames most modern medical activity, says that research is justified if the population from whom participants are drawn would benefit from the results. The thought behind this is that a new AIDS drug shouldn’t be tested on people in Africa, for example, who could never afford to buy it. But uninsured unemployed people in the US do not have access to expensive medical treatments either, so it’s not clear that they could benefit from this research. On top of that, most agencies don’t offer free treatment to injured subjects, and none give them compensation for suffering or lost wages.

This is a strange underworld that has been brought to light for the academic community by Carl Elliot, an ethicist, and Robert Abadie, an anthropologist who lived among phase 1 participants for his PhD.
⁴
The industry refers to these participants by the oxymoron ‘paid volunteers’, and there is a universal pretence that they are not paid for their work, but merely reimbursed for their time and travel expenses. The participants themselves are under no such illusions.

Payment is often around $200 to $400 a day, studies can last for weeks or more, and participants will often do several studies in a year. Money is central to the process, and payment is often back-loaded, so you only receive full payment if you complete the study, unless you can prove your withdrawal was due to serious side effects. Participants generally have few economic alternatives, especially in the US, and are frequently presented with lengthy and impenetrable consent forms, which are hard to navigate and understand.

You can earn better than the minimum wage if you ‘guinea pig’ full-time, and many do: in fact, for many of them it’s a job, but it’s not regulated as any other job might be. This is perhaps because we feel uncomfortable regarding this source of income as a profession, so new problems arise. Participants are reluctant to complain about poor conditions, because they don’t want to miss out on future studies, and they don’t go to lawyers for the same reason. They may be disinclined to walk away from studies that are unpleasant or painful, too, for fear of sacrificing income. One participant describes this as ‘a mild torture economy’: ‘You’re not being paid to do a job…you’re being paid to endure.’

If you really want to rummage in this underworld, I recommend a small photocopied magazine called
Guinea Pig Zero
. For anyone who likes to think of medical research as a white-coated exercise, with crisp protocols, carried out in clean glass-and-metal buildings, this is a rude awakening.

    The drugs are hitting the boys harder than the girls. The ephedrine is not so bad, it’s like…over the counter speed. Then they increased our dosage and things got funky. This is when the gents took to the mattresses…We women figured we had more endurance…No. 2 was feeling so bad that he hid the pills under his lounge during the dosing procedure. The coordinator even checked his mouth and he still got away with it…this made No. 2 twice as sick after the next dosing – he couldn’t fake it for the rest of the study.
⁵

Guinea Pig Zero
published investigations into deaths during phase 1 trials, advice for participants, and long, thoughtful discursions on the history of guinea-pigging (or, as the subjects themselves call it, ‘our bleeding, pissing work’). Illustrations show rodents on their backs with thermometers in their anuses, or cheerfully offering up their bellies to scalpels. This wasn’t just idle carping, or advice on how to break the system. The volunteers developed ‘research unit report cards’ and discussed unionising: ‘The need exists for a set of standard expectations to be set down in an independently controlled, guinea-pig based forum so we volunteers can rein in the sloppy units in a way that doesn’t bring ourselves harm.’

These report cards were informative, heartfelt and entertaining, but as you might expect, they were not welcomed by the industry. When three of them were picked up by
Harper’s
magazine, it resulted in libel threats and apologies. Similarly, following a Bloomberg news story from 2005 – in which more than a dozen doctors, government officials and scientists said the industry failed to adequately protect participants – three illegal immigrants from Latin America said they were threatened with deportation by the clinic they had raised concerns about.

We cannot rely solely on altruism to populate these studies, of course. And even where altruism has provided, historically, it has been in extreme or odd circumstances. Before prisoners, for example, drugs were tested on conscientious objectors, who also wore lice-infested underpants in order to infect themselves with typhus, and participated in ‘the Great Starvation Experiment’ to help Allied doctors understand how we should deal with malnourished concentration camp victims (some of the starvation subjects committed acts of violent self-mutilation).
⁶

The question is not only whether we feel comfortable with the incentives and the regulation, but also whether this information is all new to us, or simply brushed under the carpet. You might imagine that research all takes place in universities, and twenty years ago you’d have been correct. But recently, and very rapidly, almost all research activity has been outsourced, often far away from universities, into small private clinical research organisations, which sub-contract for drug companies, and run their trials all around the world. These organisations are atomised and diffuse, but they are still being monitored by frameworks devised to cope with the ethical and procedural problems arising in large institutional studies, rather than small busi nesses. In the US, in particular, you can shop around for Institutional Review Board approval, so if one ethics committee turns you down, you simply go to another.

This is an interesting corner of medicine, and phase 2 and 3 trials are being outsourced too. First, we need to understand what those are.

Phase 2 and 3

So, you’ve established that your drug is broadly safe, in a few healthy people referred to by popular convention as ‘volunteers’. Now you want to give it to patients who have the disease you’re aiming to treat, so you can try to understand whether it works or not.

This is done in ‘phase 2’ and ‘phase 3’ clinical trials, before a drug comes to market. The line between phase 2 and 3 is flexible, but broadly speaking, in phase 2 you give your drug to a couple of hundred patients, and try to gather information on short-term outcomes, side effects and dosage. This will be the first time you get to see if your blood-pressure drug does actually lower blood pressure in people who have high blood pressure, and it might also be the first time you learn about very common side effects.

In phase 3 studies you give your drug to a larger group of patients, usually somewhere between three hundred and 2,000, again learning about outcomes, side effects and dosage. Crucially, all phase 3 trials will be randomised controlled trials, comparing your new treatment against something else. (All of these pre-marketing trials, you will notice, are in fairly small numbers of people, which means that rarer side effects are very unlikely to be picked up. I’ll come back to this later.)

Here again, you may be wondering: who are these patients, and where do they come from? It’s clear that trial participants are not representative of all patients, for a number of different reasons. Firstly, we need to consider what drives someone to participate in a trial. It would be nice to imagine that we all recognise the public value of research, and it would be nice to imagine that all research had public value. Unfortunately, many trials are conducted on drugs that are simply copies of other companies’ products, and are therefore an innovation designed merely to make money for a drugs company, rather than a significant leap forward for patients. It’s hard for participants to work out whether a trial they’ve been offered really does represent a meaningful clinical question, so to an extent we can understand people’s reluctance to take part. But in any case, wealthy patients from the developed world have become more reluctant to participate in trials across the board, and this raises interesting issues, both ethical and practical.

In the US, where many millions of people are unable to pay for health care, clinical trials are often marketed as a way to access free doctors’ appointments, scans, blood tests and treatment. One study compared insurance status in people who agreed to participate in a clinical trial with those who declined;
⁷
participants are a diverse population, but still, those agreeing to be in a trial were seven times more likely to have no health insurance. Another study looked at strategies to improve targeted recruitment among Latinos, a group with lower wages, and poorer health care, than the average:
⁸
96 per cent agreed to participate, a rate far higher than would normally be expected.

These findings echo what we saw in phase 1 trials, where only the very poor were offering themselves for research. They also raise the same ethical question: trial participants are supposed to come from the population of people who could realistically benefit from the answers provided by that trial. If participants are the uninsured, and the drugs are only available to the insured, then that is clearly not the case.

But selective recruitment of poor people for trials in the USA is trivial compared to another new development, about which many patients − but also many doctors and academics – are entirely ignorant. Drug trials are increasingly outsourced around the world, to be conducted in countries with inferior regulation, inferior medical care, different medical problems and – in some cases – completely different populations.

‘CROs’ and trials around the world

Clinical research organisations are a very new phenomenon. Thirty years ago, hardly any existed: now there are hundreds, with a global revenue of $20 billion in 2010, representing about a third of all pharma R&D spending.
⁹
They conduct the majority of clinical trials research on behalf of industry, and in 2008 CROs ran more than 9,000 trials, with over two million participants, in 115 countries around the world.

This commercialisation of trials research raises several new concerns. Firstly, as we have already seen, companies often bring pressure to bear on academics they are funding, discouraging them from publishing unflattering results and encouraging them to put spin on both the methods and the conclusions of their work. When academics have stood up to those pressures, the threats have turned into grim realities. What employee or chief executive of a CRO is likely to stand up to a company which is directly paying the bills, when the staff all know that the CRO’s hope for future business rides on how it manages each demanding client?

It’s also interesting to note that the increasing commercial-isation of research has driven many everyday clinicians away from trials, even when the trials come from the more independent end of the spectrum. Three British academics have written recently of their difficulty in getting doctors to help them recruit patients for a study requested by the European medicines regulator, but paid for by Pfizer: ‘Academics wrote the protocols, collaborators are academic, and the study data are owned by the steering committees (on which industry has no say), which also control analyses and publications. A university is the sponsor. Funding is from industry, which has no role in study conduct, data collection, or data interpretation.’
¹⁰
UK doctors and primary care trusts regarded this study as commercial, and were reluctant to hand over their patients. They are not alone. The Danish Board of Medicine regards these kinds of studies as commercial, which means that any practice participating in them must declare the interest, further reducing recruitment. In the US, meanwhile, the use of private community doctors to conduct trials has expanded enormously, with incentives approaching $1 million a year for the most enterprising medics.
¹¹

For a window into the commercial reality of the CRO world, you can look at the way these services are presented when they are being promoted to pharmaceutical companies, and see how far this reality is from the needs of patients, and any spirit of neutral enquiry. Quintiles, the largest company, offers to help its industry customers to ‘better identify, promote, and prove the value of a particular drug to key stakeholders’.
¹²
‘You’ve spent hundreds of millions of dollars and years bringing your product through the drug development process,’ it says. ‘Now you face multiple opportunities – and possibly more requirements – to demonstrate safety and effectiveness in larger populations.’ There are also cases of CROs and drug companies with contracts that share the risk of a poor outcome between them, increasing the chances of a conflict of interest even further.

These aren’t smoking guns. They simply illustrate the banal commercial reality of what these companies do: they find stuff out, of course, but their main objective is to make a company’s drug look good so that regulators, doctors and patients will swallow it. That’s not ideal in science. It’s not fraud either. It’s just not ideal.

It would be wrong to imagine that this shift in culture has been driven by a hope that CROs would produce more flattering findings than other options. They are attractive because they’re fast, efficient, focused and cheap. And they’re especially cheap because, like many other industries, they outsource their work to poorer countries. As the former chief executive of GSK explained in a recent interview, running a trial in the US costs $30,000 per patient, while a CRO can do it in Romania for $3,000.
¹³
That is why GSK aims to move half of its trials to low-cost countries, and it is part of a global trend.