The problem with industry-funded drug trials

How much can we trust the results of clinical trials, especially ones that have been funded by companies with vested interests? This is the question we should continually ask ourselves, after the debacle of Seroxat.

The active ingredient of Seroxat is paroxetine. Medicines are known by two names, one of the active ingredient, the one that gives it the scientific name, and the other, the brand name. For example, the ingredient paracetamol is marketed under Neurofen, among other names. Companies that manufacture their own brand of medicine may decide to market it little more than their company name before the active ingredient, for example, Tesco paracetamol or Boots Ibuprofen, in order to distinguish it from other rival brands and aligning it with an already recognised scientific name, but without the associated costs of having to launch a new product brand.

Paroxetine is an anti-depressant and made its name as one of the few anti-depressants to be prescribed to children. However it was withdrawn from use after re-examination of the original scientific evidence found that the results published in the original research were misleading and had been misconstrued.

The prescription of medications to children is done under caution and monitoring, as there are various risks involved. Firstly, there is the danger that their bodies adapt to the medication and become resistant, thereby necessitating either higher doses in adult life, or a move on to stronger medication. In this instance there is the possibility that rather than addressing the problem, the medication only becomes a source of life-long addiction to medication. The second risk is that all medicines have side effects and can cause irreparable damage to the body in other regions. For example, the use of aspirin in the elderly was found to damage the lining of the stomach.

Equally worrying is the effect of these drugs on the health of the mind. Some drugs, particular those for mental health, are taken for their calming effect on the mind. The two main types of mental health drugs can be said to be anti-depressants and mood stabilisers, and while the aim of these drugs is to limit the brain’s overactivity, some have been found to trigger suicidal thoughts in users instead, ironically performing the function they were meant to discourage.

Children are often currently either prescribed adult medication in smaller doses of half strength instead, but the difficulty in assessing the dosage is that it does not lend itself to being analysed on a straight line graph. Should children under a certain age, say twelve for example, be prescribed as doseage based on age? Or if the most important factor in frequency is the body’s ability for absorption, should we prescribe based on other factors such as body mass index?

So when Seroxat came on to the market marketed as an anti-depressant for children you could almost feel the relief of the parents of the young sufferers. A medical product, backed by science and research, suitable for children, approved by the health authorities. Finally a medical product young sufferers could take without too much worry, and one – having been tested with young children – that parents could be led to surmise would be effective in managing their children’s mental health.

Except that Paroxetine, marketed as Seroxat, was not what it claimed to be. It has been withdrawn from use after scientists found, upon re-analysing the original data, that the harmful effects, particularly on young people were under-reported. Furthermore, researchers claim important details that could have affected the approval of its license were not made public, because it might have meant years of research might have gone down the drain.

When a medical product is launched, it is covered under a twenty-year no-compete patent, which means that it has a monopoly on that medicine for that period. While one might question why that is so, it is to protect the time spent by the pharmaceutical companies in investing in research and marketing the product, and give it a time period to establish a sizeable market share as a reward for developing the medication.

Twenty years for a patent might seem like a long term, but as companies apply for it while the product is in the early stages of development, in order that its research is not hijacked by a competing pharmaceutical company, they are often left with a period of ten years or less by the time the medical product has some semblance of its final form. The patent company has that amount of time to apply for a license and to market and sell the medication. After the original twenty years has elapsed, other companies can enter the fray and develop their own brands of the medicine. They, of course, would not need to spend the money on research as much of the research will have already been done, published, and accessible – enough to be reverse-engineered in a shorter space of time. Pharmaceutical companies are hence always engaged in a race against time, and if a product hits a snag in trials, mass production is put on hold – and if the company is left with anything less than five years to market its product, it is usually not long enough a period to recoup research costs. And if it is less with anything less than three years, it might as well have done the research for the companies that follow, because it will not recover the costs of research and marketing. While not proven, it is believed that pharmaceutical companies hence rush out products which have not been sufficiently tested, by emphasising the positive trial results, and wait for corrective feedback from the market before re-issuing a second version. It is not unlike computer applications nowadays which launch in a beta form, relying on user feedback for improvement, before relaunching in an upgraded form. The difference is software has no immediate implications on human health. Medication does.

Researchers who re-examined data from the medical trial of the antidepressant paroxetine, found reports of suicide attempts that had not been included in the original research paper. And because the makers of paroxetine, GlaxoSmithKline (GSK), had marketed paroxetine as a safe and also effective antidepressant for children, even though evidence was to the contrary, GSK had to pay damages for a record $3 billion for making false claims.

In the original research trials, GSK claimed that paroxetine was an effective medication for treating adolescents with depression and it was generally well-tolerated by the body with no side effects. Subsequent analysis found little advantage from paroxetine and an increase in harm in its use, compared to placebo.

The whole issues highlights the difficulty in trusting medical trials whose data is not independently accessed and reviewed.

The current stance on data is that pharmaceutical companies can select that clinical data they choose to release. Why is this so? We have already covered the reason for this. They have committed funds to research and are hence protective (and have right to be) protective of the raw data generated, particularly when competitors are waiting in the fold to launch products using the same data.

If you were a recording artist, and hired a recording studio for two weeks, musicians to play for you and sound engineers to record your work, at the end of the two weeks, you might have come up with a vast amount of recordings which will undergo editing, and from which your album will be created, then whatever has been recorded in the studio is yours, and you have the right to be protective about it in order that someone else might not release music using your ideas or similar to yours.

The problem is that when the pharmaceutical company initiating and funding the research is the one that will eventually market it first, and the clock is ticking against it, then it has a vested interest in the success of the product and is inherently biased to find positive outcomes that are advantageous to the product it creates.

Who would commit twenty years of time, research, marketing and finance to see a product fail?

The pharmaceutical company is also pressured to find these outcomes quickly and hence even the scientific tests may be already geared to ones that lead to pre-determined conclusions rather than ones that open it up to further analysis and cross-examination, and take up precious time or cause delay.

This creates a situation where only favourable data has been sought in the trials and only such data is made publicly available, leading to quick acceptance of the drug, a quick acquisition of a license and subsequently less delay heading into the marketing process.

The alternative is for independent review of the raw data, but this causes additional stresses on the time factor, and the security of the raw data cannot be guaranteed.

Despite the limitations of the current system, there are attempts to reform the system. The AllTrials campaign is a pressure group seeking independent scrutiny of medical data and has backing by medical organisations. The AllTrials group argue that all clinical trial data should be made available for the purpose of independent scrutiny in order to avoid similar issues to the misprescribing of paroxetine from repeated occurrence in the future.

The original study by GSK reported that in clinical trials 275 young people aged 12 to 18 with major depression were randomly allocated to either paroxetine, an older antidepressant drug called imipramine, or a placebo for eight weeks.

The researchers who reviewed the previous original study in 2001 found that it seriously under-reported cases of suicidal or self-harming behaviour, and that several hundreds of pages of data were missing without clear reason. It is likely these did not look upon paroxetine favourably.

Data was also misconstrued. For example, the 2001 paper reported 265 adverse events for people taking paroxetine, while the clinical study report showed 338.

The data involved examining 77,000 pages of data made available by GSK, which in hindsight, might have been 77,000 pages of unreliable data.

This study stands as a warning about how supposedly neutral scientific research papers may mislead readers by misrepresentation. The 2001 papers by GSK appear to have picked outcome measures to suit their results.

It subsequently come to light that the first draft paper was not actually written by the 22 academics named on the paper, but by a ghostwriter paid by GSK.

That fine for GSK might be seen as small in light of this. Certainly the reliability of industry-funded clinical trials, and how the process can be overhauled, is one we need to be considering for the future.

Red wine – the media’s Wonderdrink

If there is anything to be said about the British media, it is that it seems intent to make a superhero or villain out of the common everyday foods we encounter. Every now and again we are presented with small-scale research on food or drink that promises either a miracle cure or a dangerous red flag. One assumption peddled to us is by continuing to consume the food, we will either gain added health benefit without too much effort. Miracle cure just by eating! The counter to this is the article written to warn against continued consumption. Danger food – consume carefully! You are either a superhero, or a villain in the world of miracle foods.

It is safe to assume that the purpose of these articles is ultimately to hook the reader into buying the newspaper to examine the article further. And if it appears on an online version instead, you can be sure that the intention is to keep the reader glued to the page while paid-for advertising revenue flashes on the side panels. To state it cynically, the purpose of these articles is for sales. It might be long before certain foods such as milk might purportedly be the cure to cancer.

We need not spend too much time judging how effective these media reports are. If you are looking to a newspaper as a reference for health advice, you might as well ask about ballet lessons from the petrol station.

One of the poster children for miracle foods is red wine. Depending on what you’ve read, red wine can:

  • Boost immunity
  • Prevent tooth decay
  • Save your eyesight
  • Be good for the heart

But it won’t help you in the fight against diabetes, or help you lose weight. Was worth considering, though.

One of the latest research into red wine studied if, yes, it could find the ageing process. A US study suggested resveratrol, a substance found in the skin of red grapes, may help keep our muscles and nerves healthy as we get older.

Researchers gave mice food containing resveratrol for a year, then compared the muscle and nerve cells of those mice to cells from mice the same age who’d had a normal diet. In the mice who’d had the resveratrol-enriched diet, they found less evidence of age-related changes.

The researchers also looked at another chemical, metformin, but found it had less effect.

Researchers divided laboratory-bred mice into four groups and fed them either:

  • a normal diet
  • a lower calorie diet from four months of age
  • a diet enriched with resveratrol from one year of age
  • a diet enriched with metformin from one year of age

When the mice were aged two years, they looked at their muscle and nerves, at the meeting point of the two (the neuromuscular junction, or NMJ) in a leg muscle. They also looked at the NMJs of three-month-old mice to see how they compared to the older mice.

Compared with mice fed a regular diet, those who’d been given resveratrol or who’d had a calorie-restricted diet showed:

less fragmentation of tissue at the neuromuscular junction
fewer areas where the nerve cells had degenerated, which would have meant that the muscle no longer had input from nerves

The two-year-old mice which had calorie-restricted diets had neuromuscular junctions that were most similar to the three-month-old mice. Metformin had little effect in this experiment.

The researchers say that this indicates less ageing as muscle fibres increase in size with ageing. But this does not suggest if the ageing was beneficial or not to the subject.

Resveratrol has been of interest to anti-ageing scientists for many years and researchers have previously shown it may be linked to a slowing of the decline in thinking and movement, at least in rodents. This study suggests a possible way this might happen.

But the results don’t tell us anything about what happens in humans. They suggest this substance may be useful for further research in humans at some point. They certainly don’t provide a reason to drink gallons of red wine, in the hope of seeing an anti-ageing effect. Drinking too much alcohol is a sure-fire way to speed up deterioration of thinking skills, and can cause brain damage. Too much alcohol in the long term is linked to several cancers, heart disease, stroke and liver disease.

Although red wine contains resveratrol, the amount varies widely, from around 0.2mg to 12.6mg per litre. That’s nothing like enough to get the amounts consumed in this study.

The mice were fed 400mg of resveratrol per kilogram of body weight each day. To achieve the same level of anti-ageing purported in the study, the average weight woman in the UK (around 70kg) would need 28g of resveratrol a day for the same effect. This would be obtained by consuming more than 2,000 litres of the most resveratrol-rich wine. An average weight man would need even more. This would be going beyond side effects and into the realm of health dangers! Or if you were disturbed by the daily consumption of this amount of alcohol, and still wanted to try, you could eat bin loads of berries – you might need fifty of these a day. What’s for breakfast? Blueberries. Snack? Blueberries powerbar. Lunch? Blueberry soup? Dessert? Blueberry cake. Resveratrol occurs naturally in the skins of some red fruits, including some grapes, blueberries and mulberries. But this rate, anti-ageing might be more of a curse.

The study was carried out by researchers from Virginia Tech, Roanoke College and the National Institute on Aging, all in the US, and was funded by the National Institutes of Health.

Is there any thing of value we can glean from this research? One certainly hopes that the whole research was conducted for more significance than mere paper filler.

The effects of rosveratol will probably hold the most interest for researchers. One can imagine that scientists will be looking to produce genetically-modified grapes that hold more of the chemical, or refine the chemical until it reaches higher levels of purity. Drugs, medication, and anti-ageing creams may contain higher levels of rosveratol. Why is there the interest in slowing down ageing? It extends beyond the obvious physical aging. Slowing down the process may also inhibit age-related diseases such as cancer, diabetes, Parkinson’s and dementia.

And while it was of little effect in this particular trial, metformin is currently undergoing trials as an anti-ageing drug. While it is one of the drugs used in the treatment of type 2 diabetes, and marketed under brand names such as Glucophage, it is relatively new as an anti-ageing drug.

Belgian researchers researching metformin found it increased the number of oxygen molecules released into a cell. When tested on roundworms, the worms aged slower, did not slow down, nor develop wrinkles. They grew stronger bones and increased their own lifespan by nearly 40%.

Metformin only costs only 10p a day which means it falls well under the threshold of QALY (quality-assisted life years) cost that the NHS uses to measure cost-effectiveness. It is conceivable that either metformin or rosveratol could form the active ingredient of anti-ageing pills or creams in the future.

And when that happens, you can read all about it in the papers again, about how red wine really lengthens your lifespan! You might even want to sign up for a clinical trial!

The British media is really drunk on red wine.

Why clinical trials exist, and how to sign up

A clinical trial is a research method that compares the effects of one treatment with another. The subjects of a clinical trial can be patients, healthy people, or both.

If you are interested to take part in a clinical trial, you can ask your doctor or a patient organisation if they know of any clinical trials that you may be eligible to join. Other ways of finding out including registering your interest in taking part in research online.

The UK Clinical Trials Gateway (UKCTG) website searches through different registers and pulls through information about clinical trials and other research from several different UK registers. When you sign up to it, researchers will get in touch about research that might be suitable for you.

While this is the main method of contact, you can also search the UKCTG site to find trials relevant to you, and you can contact researchers yourself.

If you are looking for something on a global basis, the World Health Organization’s Clinical Trials Search Portal provides access to clinical trials in countries all around the world.

Charities can also be a good source of clinical trials.

Some charities which look for people to take part in clinical trials include:

  • Arthritis Research UK: current clinical trials and studies
  • Cancer Research UK: find a clinical trial
  • Multiple Sclerosis Society: MS clinical trials
  • Target Ovarian Cancer: clinical trials information centre
  • Parkinson’s UK: clinical research

Why would anyone consider being a human guinea pig? If we are brutally honest, that is what it amounts to. And if we were being very honest, we might fine-tune it down to two reasons: treatment and financial incentives.

Clinical trials help doctors to understand about how they can treat a particular disease or condition. It may benefit you, or others like you, in the future. And if you participate in a clinical trial, you may be one of the first people to benefit from a new treatment. However, you must be prepared that the new treatment may turn out to be no better, or worse, than the standard treatment, and that your participation is the method through which they find out. However, you may be placed in the control group, which means you not receive any treatment, but others who do have their results compared to you – and that can be very disappointing.

Some clinical trials offer payment, which can vary from hundreds to thousands of pounds depending on what is involved and expected from you. The majority of trials however are unlikely to offer payment beyond your travel expenses.

Before you sign up to a trial, it is important to find out about the inconvenience and risks involved and to carefully weigh up whether it is worth it. You have to remember that trials can be time consuming – you may be expected to attend a number of screening and follow-up sessions, and some trials require you to stay overnight. In addition to the constraints placed on your time, there may be restrictions on what you can and cannot do – for example, you may be asked to not eat or drink alcohol for a period of time. As trials are essentially the assessment of treatment in their experimental stages, you may experience unknown side effects from the treatment.

All clinical trials of new medicines go through three or four phases to test whether they are safe and whether they work. The medicines will usually be tested against another treatment called a control and the results compared to note any significant effect. The control will either be a dummy treatment (a placebo) or a standard treatment already in use.

The first phase of the trials involves a small number of people, who may be healthy volunteers, are they are given the medicine. In this phase, the drug is being trialled in human volunteers for the first time and the purpose is for the researchers to test for side effects and calculate what the right dose might be to use in treatment. Unfortunately if the doseage is too high side effects can be uncomfortable. Researchers start with small doses and only increase the dose if the volunteers don’t experience any side effects, or if they only experience minor side effects. Sometimes the threshold to which side effects occur is sought – not nice!

In the second phase, the new medicine is tested on a larger group of people who are ill. After having passed the side effects filter, this stage is to get a better idea of its effects in the short term.

The third phase involves medicines that have passed phases one and two. These medicines are tested in larger groups of people who are ill, and then they are compared against an existing treatment or a placebo to compare the benefits or side effects. Often after this stage the treatment is examined for its cost-effectiveness as well.

Some medicines undergo a fourth trial phase while they have been passed for use. The safety, side effects and effectiveness of the medicine continue to be studied while it is being used in practice. However, this is not required for every medicine. It is only carried out on medicines that have passed all the previous stages and have been given marketing licences – a licence means the medicine can be made available on prescription. You can find out about the whole process here in greater detail.

You cannot choose which group you are put in when you are accepted for a clinical trial. You will usually be randomly assigned to either the treatment group – where you’ll be given the treatment being assessed, or the control group – where you’ll be given an existing standard treatment, or a placebo if no proven standard treatment exists.

And while the treatments are different in the two groups, researchers try to keep as many of the other conditions the same as possible, so that the effect of the treatment can be fully quantified. The conditions may extend to the trial groups. For example, both groups should have people of a similar age, with a similar proportion of men and women, who are in similar overall health. In most trials, a computer will be used to randomly decide which group each patient will be allocated to, in order to avoid human bias in selection. In many trials, nobody knows who’s been allocated to receive which treatment. This is known as blinding, and it helps reduce the effects of bias when comparing the outcomes of the treatments.

If you do express interest in a trial, a doctor or nurse is likely to tell you something about it in person before you undergo it. You’ll also be given some printed literature to take away, and if you have concerns over the trial you may come back with some questions you feel haven’t been answered.

Some questions you may ask may include:

What is the aim of the trial and how will it help people?
Who is funding the trial?
What treatment will I get if I do not take part in the trial?
How long is the trial expected to last, and how long will I have to take part?
How long will it be before the results of the trial are known?
What will happen if I stop the trial treatment or leave the trial before it ends?
What would happen if something went wrong? It’s rare for patients to be harmed by trial treatments, but you may want to ask about compensation if this were to happen.
Practical questions
How much of my time will be needed?
Will I need to take time off work?
Will I be paid?
Will the costs of my travel to take part in the trial be covered?
If the trial is testing a new drug, will I have to collect it from the hospital, will it be sent to me by post, or will I get it through my doctor?
Will I have to complete questionnaires or keep a diary?
What are the possible side effects of my treatment?
How could the treatments affect me physically and emotionally?
Who can I contact if I have a problem?
Will someone be available 24 hours a day?
How do I find out the results of the trial?

There are many questions you may have and it is best to feel fully secure before you undergo a trial. As in the case with any treatment, you can’t be sure of the outcome. And if you are part of the treatment group, you may be given a new treatment that turns out not to be as effective as the standard treatment. As with all medicines, it’s possible you’ll experience unexpected side effects. And while it is rare, you must be prepared that you may leave the trial in a slightly poorer state of health than when you entered it! You may decide to stop taking part in a trial if your condition is getting worse or if you feel the treatment isn’t helping you. Your departure can be at any point without giving a reason and without it affecting the care you receive.

A good thing to also bear in mind about trials, too, is that you may have to visit your place of treatment more often, or have more tests, treatments or monitoring, than you would if you were receiving the standard treatment in usual care.

At the end of the trial, the results are published by the researchers and are then made available to anyone who took part and wanted to know the results. If the researchers neglect to offer you the results and you want to know, you are well within your right to ask for them. Bigger agencies such as the National Institute for Health Research (NIHR), have websites where they publish the results of the research they have supported.

Trials are regulated and judged ethical by the MHRA. Before a clinical trial of a new medicine can begin, a government agency called the Medicines and Healthcare products Regulatory Agency (MHRA) needs to review and authorise it. One of the functions the MHRA performs is in inspecting sites where trials take place to make sure they’re conducted in line with good clinical practice.

Another body, the Health Research Authority (HRA) works to protect and promote the interests of patients and the public in health research. It is responsible for research ethics committees up and down the country.

All medical research involving people in the UK, whether in the NHS or the private sector, first has to be approved by an independent research ethics committee. The committee protects the rights and interests of the people who will be in the trial.

What are the benefit of clinical trials? Well, they can benefit us in many ways. For example, clinical trials can:

  • prevent illnesses by testing a vaccine
  • detect or diagnose illnesses by testing a scan or blood test
  • treat illnesses by testing new or existing medicines
  • find out how best to provide psychological support
  • find out how people can control their symptoms or improve their quality of life – for example, by testing how a particular diet affects a condition

Many clinical trials are designed to show whether new medicines work as expected. These results are sent to the MHRA, which decides whether to allow the company making the medicine to market it for a particular use. The company usually applies for a twenty year patent to cover the research and marketing of the drug exclusively.

If research has identified a new medicine, the MHRA must license it before it can be marketed. Licensing shows a treatment has met certain standards of safety and effectiveness. The safety of the medicine must be monitored carefully over the first few years of a newly licensed treatment. This is because rare side effects that weren’t obvious in clinical trials may show up for the first time.

You may not have been selected for a trial but you may express interest in the results. You can find various results of clinical trials from sources such as:

  • The Lancet medical journal
  • British Medical Journal (BMJ)
  • The New England Journal of Medicine
  • Cochrane Library – a collection of high-quality evidence
  • NHS Evidence database

Many of these publications offer abstracts, which are shorter summaries of the research. If you wish to delve deeper,
you usually have to take up a subscription to the journal. But before you do so, consider that research papers are not written in plain English and often use many medical, scientific and statistical terms which then make them possibly very difficult to understand.

The mainstream media offer a more readable version of the research. But do bear in mind, too, that while news stories are easier to read than original research papers, sometimes the findings are exaggerated or sensationalised in order to sell papers!