Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients (15 page)

This is what medicine should look like. An honest list of all the people involved, free access to information, and all the data pooled together, giving the most accurate information we can manage, to inform real decisions, and so prevent avoidable suffering and death.

We are a very, very long way away from there.

What can be done?

We urgently need to improve access to trial data. In addition to the previous suggestions, there are small changes that would vastly improve access to information, and so improve patient care.

1. The results of all trials conducted on humans must be made available within one year of completion, in summary table form if academic journal publication has not occurred. This requires the creation of a body that is charged with publicly auditing whether or not trials have withheld results at twelve months; and primary legislation that is enforced, as a matter of urgency, internationally, with stiff penalties for transgression. In my view these penalties should include fines, but also prison terms for those who are found to be responsible for withholding trial data, as patients are harmed by this process.
   
2. All systematic reviews – such as Cochrane reviews – that draw together trial results on any clinical question should also include a section on the trials which they know have been conducted, but whose results are being withheld. This should state: which completed trials have not reported results; how many patients’ worth of information there is in each unreported trial; the names of the organisations and the individuals who are withholding the data; the efforts the reviewers have made to get the information from them. This is trivial extra work, as review teams already attempt to access this kind of data. Documenting this will draw attention to the problem, and make it easier for doctors and the public to see who is responsible for harming patient care in each area of medicine.
   
3. All clinical study reports should also be made publicly available, for all the trials that have ever been conducted on humans. This will be cheap, as the only costs are in finding one paper copy, scanning it and placing it online, perhaps with a check to remove confidential patient information. There is a vast mountain of highly relevant data on drugs that is currently being withheld, distorting what we know about treatments in widespread current use. Many of these documents will be sitting in the dry paper archives of drug companies and regulators. We need legislation compelling the industry to hand them over. Our failure to fix this is costing lives.
   
4. We need to work on new methods for academics to extract summary information from these documents, as they are more detailed than published academic papers. The Cochrane group working on Tamiflu have made great progress here, learning as they go, and this field will need manuals.
   
5. We should work towards all triallists having an obligation to share patient-level data wherever possible, with convenient online data warehouses,
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   and streamlined systems whereby legitimate senior researchers can make requests for access, in order to conduct pooled analyses and double-check the results reported in published trials.
   

None of this is difficult, or impossible. Some of it is technical, for which I apologise. The field of missing data is a tragic and strange one. We have tolerated the emergence of a culture in medicine where information is routinely withheld, and we have blinded ourselves to the unnecessary suffering and death that follows from this. The people we should have been able to trust to handle all this behind the scenes – the regulators, the politicians, the senior academics, the patient organisations, the professional bodies, the universities, the ethics committees – have almost all failed us. And so I have had to inflict the details on you, in the hope that you can bring some pressure to bear yourself.

If you have any ideas about how we can fix this, and how we can force access to trial data – politically or technically – please write them up, post them online, and tell me where to find them.

2

Where Do New Drugs Come From?

Where do drugs come from?

That is the tale of hidden trial data. In the remainder of this book we will see how the pharmaceutical industry distorts doctors’ beliefs about drugs through misleading and covert marketing; we will also see how trials can be flawed by design, and how regulators fail to regulate. But first, we must see how drugs are invented in the first place, and how they come to be available for prescription at all. This is a dark art, and generally remains a mystery for both doctors and patients. There are hidden traps at every turn, odd incentives, and frightening tales of exploitation. This is where new drugs come from.

From laboratory to pill

A drug is a molecule that does something useful, somewhere in the human body,
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and luckily, there’s no shortage of such molecules. Some are found in nature, in particular from plants: this makes sense, because we share a lot of molecular make-up with plants. Sometimes you just extract the molecule, but more commonly you add a few bits onto it here and there, through some elaborate chemical process, or take a few bits away, in the hope of increasing the potency, or reducing the side effects.

Often you’ll have some idea about the mechanism you’re targeting, and usually that’s because you’re copying the mechanism by which an existing drug works. For example, there’s an enzyme in the body called cyclooxygenase, which helps to make molecules that signal inflammation. If you stop that enzyme working, it helps to reduce pain. Lots of drugs work like this, including aspirin, paracetamol, ibuprofen, ketoprofen, fenoprofen and so on. If you can find a new molecule that stops cyclooxygenase working in a laboratory dish, then it’s probably going to stop it working in an animal, and if it does that, then it’s probably going to help reduce pain in a person. If nothing disastrous has happened to animals or humans in the past when they’ve taken a drug that stops that enzyme working, then your new drug is fairly likely (though not certain) to be safe.

A new drug that operates in a completely new way is much more of a development risk, because it’s unpredictable, and much more likely to fail at every step described above. But that kind of new drug would also be a more significant move forward in medical science. We’ll discuss the tension between copying and innovating later.

One way that drugs are developed is by a process called screening, one of the most boring jobs imaginable for a young laboratory scientist. Hundreds, maybe thousands, of molecules, all of slightly different shapes and sizes, will be synthesised in the hope that they will operate on a particular target in the body. Then you come up with a lab method that lets you measure whether the drug is inducing the change you hope for – stopping an enzyme from working properly, for example – and then you try every drug out, one after the other, measuring their effects until you come up with a good one. Lots of great data is created during this period, and then thrown away, or locked in one drug company’s vault.

Once you’ve got something that works in a dish, you give it to an animal. At this point you’re measuring lots of different things. How much of the drug do you find in the blood after the animal eats the pill? If the answer is ‘very little’, your patients will need to eat giant horse pills to get an active dose, and that isn’t practical. How long does the drug stay in the blood before it’s broken down in the body? If the answer is ‘one hour’, your patients will need to take a pill twenty-four times a day, and that’s not useful either. You might look at what your drug molecule gets turned into when it’s broken down in the body, and worry about whether any of those breakdown products are harmful themselves.

At the same time you’ll be looking at toxicology, especially very serious things that would rule a drug out completely. You want to find out if your drug causes cancer, for example, fairly early on in the development process, so you can abandon it. That said, you might be OK if it’s a drug that people only take for a few days; by the same token, if it harms the reproductive system but is a drug for – let’s say – Alzheimer’s, you might be less worried (I only said less worried: old people do have sex). There are lots of standard methods at this stage. For example, it can take several years to find out if your drug has given living animals cancer, so even though you need to do this for regulatory approval, you’ll also do early tests in a dish. One example is the Ames test, which lets you see if a drug has caused mutation in bacteria very quickly, by looking at what kinds of food they need to survive in a dish.

It’s worth noting at this point that almost all drugs with desirable effects will also have unintended toxic effects at some higher dose. That’s a fact of life. We’re very complicated animals, but we only have about 20,000 genes, so lots of the building blocks of the human body are used several times over, meaning that something which interferes with one target in the body might also affect another, to a greater or lesser extent, at a higher dose.

So, you’ll need to do animal and lab studies to see if your drug interferes with other things, like the electrical conductivity of the heart, that won’t make it popular with humans; and various screening tests to see if it has any effect on common drug receptors, rodents’ kidneys, rodents’ lungs, dogs’ hearts, dogs’ behaviour; and various blood tests. You’ll look at the breakdown products of the drug in animal and human cells, and if they give very different results you might try testing it in another species instead.

Then you’ll give it in increasing doses to animals, until they are dead, or experiencing very obvious toxic effects. From this you’ll find out the maximum tolerable dose in various different species (generally a rat or other rodent, and a non-rodent, usually a dog), and also get a better feel for the effects at doses below the lethal ones. I’m sorry if this paragraph seems brutal to you. It’s my view – broadly speaking, as long as suffering is minimised – that it’s OK to test whether drugs are safe or not on animals. You might disagree, or you might agree, but prefer not to think about it.

If your patients are going to take the drug long-term, you’ll be particularly interested in effects that emerge when animals have been taking it for a while, so you’ll generally dose animals for at least a month. This is important, because when you come to give your drug to humans for the first time, you can’t give it to them for longer than you’ve given it to animals.

If you’re very unlucky, there’ll be a side effect that animals don’t get, but humans do. These aren’t hugely common, but they do happen: practolol was a beta-blocker drug, very useful for various heart problems, and the molecule looks almost exactly the same as propranolol (which is widely used and pretty safe). But out of the blue, practolol turned out to cause something called multi-system oculomucocutaneous syndrome, which is horrific. That’s why we need good data on all drugs, to catch this kind of thing early.

As you can imagine, this is all very time-consuming and expensive, and you can’t even be sure you’ve got a safe, effective drug once you’ve got this far, because you haven’t given it to a single human yet. Given the improbability of it all, I find it miraculous that any drug works, and even more miraculous that we developed safe drugs in the era before all this work had to be done, and was technically possible.

Early trials

So now you come to the nerve-racking moment where you give your drug to a human for the first time. Usually you will have a group of healthy volunteers, maybe a dozen, and they will take the drug at escalating doses, in a medical setting, while you measure things like heart function, how much drug there is in the blood, and so on.

Generally you want to give the drug at less than a tenth of the ‘no adverse effects’ dose in the animals that were most sensitive to it. If your volunteers are OK at a single dose, you’ll double it, and then move up the doses. You’re hoping at this stage that your drug only causes adverse effects at a higher dose, if at all, and certainly at a much higher dose than the one at which it does something useful to the expected target in the body (you’ll have an idea of the effective dose from your animal studies). Of all the drugs that make it as far as these phase 1 trials, only 20 per cent go on to be approved and marketed.

Sometimes – mercifully rarely – terrible things happen at this stage. You will remember the TGN1412 story, where a group of volunteers were exposed to a very new kind of treatment which interfered with signalling pathways in the immune system, and ended up on intensive care with their fingers and toes rotting off. This is a good illustration of why you shouldn’t give a treatment simultaneously to several volunteers if it’s very unpredictable and from an entirely new class.

Most new drugs are much more conventional molecules, and generally the only unpleasantness they cause comes from nausea, dizziness, headache and so on. You might also want a few of your test subjects to have a dummy pill with no medicine in it, so you can try to determine if these effects are actually from the drug, or are just a product of dread.

At this moment you might be thinking: what kind of reckless maniac gives their only body over for an experiment like this? I’m inclined to agree. There is, of course, a long and noble tradition of self-experimentation in science (at the trivial end, I have a friend who got annoyed with feeding his mosquitoes the complicated way, and started sticking his arm in the enclosure, rearing a PhD on his own blood). But the risks might feel more transparent if it’s your own experiment. Are the subjects in first-in-man trials reassured by blind faith in science, and regulations?

Until the 1980s, in the US, these studies were often done on prisoners. You could argue that since then such outright coercion has been softened, rather than fully overturned. Today, being a guinea pig in a clinical trial is a source of easy money for healthy young people with few better options: sometimes students, sometimes unemployed people, and sometimes much worse. There’s an ongoing ethical discussion around whether such people can give meaningful consent, when they are in serious need of money, and faced with serious financial inducements.
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This creates a tension: payments to subjects are supposed to be low, to reduce any ‘undue inducement’ to risky or degrading experiences, which feels like a good safety mechanism in principle; but given the reality of how many phase 1 subjects live, I’d quite like them to be paid fairly well. In 1996 Eli Lilly was found recruiting homeless alcoholics from a local shelter.
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Lilly’s director of clinical pharmacology said: ‘These individuals want to help society.’