Science and the great biomedical lottery

by Jerome Burne

What exactly counts as evidence in medicine? Everyone is obviously in favour establishing a scientific basis for treatments and against drug companies hiding unfavourable trial results – see this recent report on HealthinsightUK. For self-styled sceptics who gleefully dismiss anyone practising or supporting non drug approaches to health and healing as quacks that’s about all there is to it.

A common sceptic claim runs something like this:  “Medicine tries to follow the scientific method…SCAM (ho ho) does not follow the scientific method. It holds to the old folk ways of anecdote, tradition, “sympathetic magic” and so on.” It’s a view which conjures up a sort of idealised medical UKIP world where objective science and evidence rules with an impartial empirical hand. 

The biomedical lottery

Unfortunately for the rest of us today’s medical research is not driven by an abstract search for objective truth but by the need to produce a product. Unless there is a drug at the end of promising new line of research it’s unlikely to attract funding from the biggest payers – the drug companies. Instead it will be parked with the comment that it needs more research, the funding for which will be virtually impossible to obtain, however effective it is.

So drug research rather than being a scientific project aimed at preventing or curing disease, uses science as the engine for a giant biomedical lottery that can earn the winners billions, although the tickets are paid for by patients.

Several recent posts by HealthInsightUK contributors illustrate the way that multinational pragmatism rather than unbiased empiricism rules.

For instance, a basic scientific principle is that you abandon a hypothesis when its not supported trials and tests. The failure of the companies and doctors to do this in the case of blockbuster drugs such as statins – used to cut your level of cholesterol to lower your risk of heart disease – has long been tracked by Dr Malcolm Kendrick.

“I have seen evidence that directly refutes this hypothesis again and again and again and… indeed… again. I can produce far more evidence contradicting it, than supporting it,” he posted on his blog earlier this month. “Yet still it stands, untouched (and indeed has mutated into something hugely complicated).

The mutating hypothesis

“Now we have ‘good’ cholesterol and ‘bad’ cholesterol, and ‘light and fluffy’ bad cholesterol and ‘small and dense’ bad cholesterol (which really should be called ‘evil’ cholesterol, I suppose). We have the ratio of good to bad cholesterol, apob-100 levels, particle numbers, sub-fractions of good cholesterol, dyslipidaemia, LDL particle size, or number, or… the list goes on and on.

“I have come to realise that this constant creation of new types of cholesterol, and sub-fractions, and ratios, is all part of the game that is played to protect the cholesterol hypothesis from refutation. How can you refute a hypothesis that can change into any shape it likes? Answer, you can’t.” But most doctors still maintain that all statin use us is well supported by science.

But if medical treatments lived and died according to the quality of their evidence, a drug such as the anti-depressant Cymbalta (duloxetine) would not be the number four on the drug best seller list in the USA.

It’s licenced for depression, anxiety, fibromyalgia, neuropathic pain and incontinence and it may soon get a licence for arthritis and back pain. “This is so-called indication creep,” writes BMJ columnist Dr Des Spence in the current issue. “(It) broadens pharmaceutical companies’ potential for profit, which is certainly good business if not good medicine.”

Not clinically detectable or relevant

This is because chronic pain is a valuable market but one where the bar for evidence of effectiveness is set pretty low, as Dr Spence explains: “Pain research uses myriad soft rating scores that patients report themselves. These are converted into numbers to enable the production of statistically significant outcomes—even if they are not clinically detectable or relevant.”

So duloxetine will have jumped through all the scientific hoops yet, as Spence makes clear, this drug is unlikely to be a valuable addition to a clinician’s armoury. It is only marginally more effective than a placebo (all pain treatments have a strong placebo response), scoring at about a single point more effective on a 1-10 rating scale.

It is also a drug that patients will be taking for years yet those in the trials were only followed up for a few months. “Where are the hard objective data of long term benefit?” he asks.

Not only is the evidence not hard, the balance between benefit and risk is remarkably close. For each person who benefits, according to one of the trials, six or seven people need to take it. However for every 8 people who are treated, one will suffer side effects.

This looks like bad medicine

These include being hard to come off; stories of people’s problems with withdrawal choke the internet. “The rapid rise of any psychoactive drug for multiple medically unexplained symptoms surely looks like bad medicine,” Dr Spence concludes. And yet it is clearly a winner in the biomedical lottery.

So medicine’s scorecard for “trying” to follow a scientific approach is hardly impressive. But what about the “old folk ways” that CAM supposedly clings to? Dieticians are usually held up as being on the scientific side healthy eating while clinical nutritionists are lumped with the other CAM unreliables.

However in a post just before Christmas Dr John Briffa challenged all-too familiar advice on carbohydrates that has recently been reinforced on the NHS Choices website. This restates the long running claim that carbohydrates should make up the largest portion of a healthy balanced diet and promotes bread, pasta, potatoes and rice as foods that can help you lose weight, providing you keep fat intake low.

Dr. Briffa sweeps aside these claims: “There is absolutely no recognition in this article … of the influence of hormones such as insulin and leptin on fat storage, and the differing effects of the major macronutrients (e.g. fat and carbohydrate) … In fact, there is abundant evidence to show that low-carb diets generally satisfy far more effectively than high-carb one.”

Nutritional Flat Earth Society

He concludes with a flourish: “To my mind, dietician Sian Porter and the NHS Choices website have done an appalling job of communicating the facts and summarising the evidence. For me, the article reads like a missive from the nutritional flat-Earth society.”

Could “folklore” clinical nutrition, which has long abandoned such dietician’s homilies as the low fat diet and that calories in should equal calories out be the ones practising in the most scientific way?

The logical flaw in attempting draw a line between scientific medicine (good) and CAM (bad) is in assuming that what is scientific is automatically valuable. Science is value free. It is a tool, a technique, a way of gathering information which can be put to good or bad ends. It can result in both bombs and bariatric surgery.

The crisis facing medicine at the moment is how to deal with the epidemic of metabolic disorders such as obesity, diabetes, Alzheimer’s and cancer. What links them all is lifestyle, so a sensible way to slow or  even reverse the rise would be to put some of the resources devoted to winning the biomedical lottery into equally science-based public health programs to develop the most effective forms of exercise or new ways of tailoring diets.

In practice funding for most clinical trials comes from drug companies who are understandably not remotely  interested, which leaves drugs holding all the science cards, however faulty or fraudulent. But there is nothing inevitable about this arrangement; it’s ultimately a political decision. Right now the hunt is on for new pills that replicate the benefits of lifestyle change.

Press releases trumpet the discovery of  genes that get turned on or off during exercise or when cutting back on calories. Doing the same things with drugs, they say, might make you live longer, as well as treating obesity, diabetes, neurodegenerative disorders and cancer. The very limited success of targeting biochemical switches to lose weight suggests this approach is fraught with problems and prone to nasty side effects.

But the research is done under the umbrella of science and prizes from this lottery will be huge. Meanwhile the number of people with metabolic disorders will continue to rise.

Jerome Burne

Jerome Burne

Jerome Burne is the editor of HealthInsightUK. He is an award-winning journalist who has been specialising in medicine and health for the last 10 years and now works mainly for the Daily Mail. His most recent book “10 Secrets of Healthy Ageing” was written with nutritionist Patrick Holford. He blogs at “Body of Evidence” – jeromeburne.com. 2015: Finalist for 'Blogger of the Year' award from Medical Journalists' Association.

6 Comments

  • As a member of UKIP, I am a little puzzled how our party relates to this issue (in the first paragraph). Either there is a medical acronym with the same letters, or this is a reference to the fact that UKIP is more willing to re-think commonly held dogma that seems to be leading us astray!

    Asking people to rate pain on an uncalibrated 1-10 scale, seems utterly absurd – particularly when I imagine most of us have never experienced the worst pain. Is there really no alternative – such as observing the brain’s reaction to pain in an MRI machine, or measuring skin conductance?

    • Editorial

      This was using UKIP as a metaphor for a group promotes ideas that that have little connection with the way things are now – women not so good at business as men, immigrants to be feared and kept out, pandering to homosexuals will cause punishment by climate, no truck with human rights laws. I’m sure you totally reject this as a metaphor but I’m pleased that you reading the blog and are critical of the way current regulation allows science to be put to work in support of drugs that are of marginal value.

  • Without driving this debate any further off topic, I would just like to point out that David Silvester, who made those comments about homosexuals, has been suspended from UKIP. Every party has mavericks – the important thing is to root them out! I could write at length about your other points, which also rather miss the point, but I won’t because I want to keep this debate on topic. After all, I originally came to this blog to report the unpleasant effects of Simvastatin on my polio leg – not to debate politics!

    I am still curious about the issue of pain assessment. Is there no more objective way to measure pain than to use a totally uncalibrated subjective scale?

    • Editorial

      Thanks for keeping on topic! Confess dig at UKIP a bit gratuitous. Approach to pain taken by a doctor I spoke to last week re a new arthritis treatment was to advise patients to do whatever works for them, regardless of whether approved or not. Quoted his wife who took paracetamol with great success even though official line is not to recommend it because fewer than 15% benefit according to trials. What makes developing some objective biomarker test of pain so hard, as I understand it, is that people’s responses are so varied. In the case of arthritis some people show up under scans as having a lot of damage, loss of cartilage, and report lots of pain, while others with very similar rate of damage say all is fine.

  • I must concede I did not know what to read into the reference to UKIP.

    That aside David Bailey asks a pertinent question, is there a more empirical way we can assess and describe pain?

    On the occasions I have been requested to rate my pain on the scale it has been in the context of attending A&E and an initial triage consultation. The purpose of the triage consultation is consider an early diagnose on the basis of two things, what inquiries and investigations may follow to result in diagnose and treatment, first, and with what degree of urgency, second. David is correct, asking a patient to rate pain on an arbitrary scale is a bit crude, yet it may be a simple tool that aids diagnosis. A patient that reports a a sever headache but rates pain at 9 or 10 on the scale may appreciate timely administration of pain relief but also deserves urgent investigation for the cause, amongst the possibilities to consider is brain haemorrhage, for instance. Mostly though the pain scale aids busy A&E departments prioritise their patients, we should think.

    It has been postulated that all pain is evidence of inflammation. If you like, inflammation is the event that triggers the signalling of pain.

    I think it is fair to say that pain and inflammation are each bio-electrical in their origin, and that they associate closely with the involvement of biochemical species that may carry positive charge through having been stripped of one or more electrons. A lot of biochemical dealings involve the exchange of electrons, perhaps directly, but frequently involving the exchange or reactions of hydrogen ions (H+) and hydroxide ions (OH-). Sometimes these dealings get referred to as reduction and/or oxidation, or ‘redox’ transactions. ‘Redox’ dealings can look a bit like double entry book-keeping, if there is a credit in one account there is a corresponding debit in another, and in biochemistry it is ‘ions’ that keep account.

    Pain and inflammation may result when biochemicals carrying positive charge congregate and proliferate in an area that has been subjected to some trauma or other compromise, and its likely these may conform to the category of reactive oxygen species (ROS) or ‘free radicals’.

    When you mow the grass fluids in the grass are exposed to the air and become oxidised. These oxidised derivatives of biochemicals form the basis of a rudimentary nervous system in the grass, in a sense it ‘knows’ it has been cropped and is stimulated into new growth. Oxidation triggers an adaptive response in something so dumb as grass. When you cut your finger it stings. Blood is exposed to the air and some factions of it will become oxidised. Straight away the physiological response in proximity to the cut is to guard against infection, stem the loss of blood, and signal to cells they must set about repairing the damage. You can see how oxidation of certain components in blood may set the initial wheels in motion. I haven’t checked, but I’d guess ROS are what send signals of pain.

    In theory you could test the blood for the presence of ROS, or you could test for markers that indicate the presence of inflammation. In chronic disease C-reactive protein (CRP) is made out to be one such marker. In practice it’s how various indications lead to a diagnosis that matters so trying to scale the pain is generally helpful and an arbitrary scale is adequate enough.

    But there is another tool. The presence of ROS generates heat, that’s what inflammation is, in a sense, and it makes sense that energy and it’s transfer is what leads to increased heat. It is. least it may be, increased trading of electrons that generates the heat that associates with inflammation. It’s the same kind of basic physics that warms a heating element.

    Thermography is the posh name for thermal imaging. Thermal imaging is the business of using infra red cameras to take a picture of heat, marry that with sophisticated computer technology and you can produce a thermogram or thermographic image which takes the data from an infra red picture and enhances subtle variations in temperature and enhances them as contrasting colours. Greens and blues are generally there to describe relatively cool while yellows, oranges, reds and even whites indicate the hotspots.

    Take a thermographic image of a blade of grass before and after cropping and my guess is you’ll see a hotspot after cropping. Do the same with your finger after it found the edge of that sharp knife hidden in the washing up bowl and it’ll reveal the same. Image a patient complaining of pain in the hip (from arthritis perhaps) and inflammation will be indicated by the thermographic hotspots.

    The pain scale is not utterly absurd, it is helpful in context. It also guards against making over use of precious screening resources. However in context my wife was sent for a timely scan after she was admitted complaining of headache and nausea, and the timely scan diagnosed sub-arachnoid haemorrhage (SAH). In her words the pain was like a bomb going off in her head. Thanks to the triage she received at Stepping Hill, and the treatment and care she received at Salford Royal, she has made a remarkable recovery. Her neurologist inspired confidence in many ways, but in a post-release consultation he advised she should monitor her cholesterol which is dumb thing to say.

    Pure cholesterol would likely contribute to tissue strength and vascular health, and while the cause of SAH remains a bit of a mystery homocysteine is implicated, in turn that implicates possible oxidative stress conveyed by homocysteine acting upon pure cholesterol to result in oxidised cholesterol, and oxidised cholesterol may then alter the behaviour of cells weakening vascular tissues in the brain, leading to aneurysm and a ‘bleed’. At the other end of homocysteine’s involvement is cortisol’s established capacity elevate homocysteine levels if levels of cortisol rise. In English this means chronic stress could be a factor contributing to risk of SAH rather more than is modest elevation of lipoprotein fractions.

    It is lamentable that you were prescribed Simvastin David.

    The way statins work invites prospects of complications, and the fact it had detrimental effect upon your polio leg is concerning. Stains do next to no good against the claims made for them, but they invite mush risk of harm. Cholesterol is not atherogenic, and we’ve known this since 1974, so waging war on cholesterol isn’t actually fighting the enemy. The ‘enemy’ is the prospect that cholesterol may suffer oxidative stress and become oxidised to oxycholesterol, and this prospect seems to be able to adversely impact upon the behaviour of cells in the tissues of the arterial wall. Cortisol and homocysteine seem to lead the risks of cholesterol becoming oxidised to oxycholesterol. The protocols directed to lowering our cholesterol cannot actually do any good, they do not interfere in the part of the process that raises the risks of developing heart disease.

    The decision to prescribe statins is not one that could ever be particularly effective, but is one that has been especially profitable.

    You say you did not drop by to debate politics, but if patients are being prescribed drugs without a mandate of evidence, where claims have been overstated and drawbacks and risks very much understated, and in the presence of rapidly emerging clarity upon what does and does not cause heart disease, if this status quo does not deserve to be elevated to the top of the political agenda, then I barely know what does.

    I guess it is the perpetual affront on the truth that had Jerome conceive of Health Insight UK as blog and comment forum where the lies and absurdities could be exposed for what they are.

  • Christopher,

    Thanks for that very detailed reply, and I am happy to report that by now my leg is as good as it used to be!

    My simvastatin experience told me a number of things.

    1) Muscle (and other) side-effects are definitely not rare – almost every other person I talked to about my problem reported something similar!

    2) Originally I was told that any side effects would likely show up within 3 weeks of starting. I had been taking simvastatin for 3 years before it struck. Although the doctor agreed it was a good idea to try stopping the simvastatin, the idea came from me – not him. I stopped and started 3 times before I was ready to blame the statin. Each time I stopped, the pain started to ease, and it took about a week of simvastatin to bring the problem back again.

    3) Even though the pain eased considerably when I stopped, it took about 10 months to vanish completely – clearly there was some serious damage to clear up.

    4) ‘Muscle pains’ hardly begins to describe the sensation, which included some severe cramps and weakness – it was very debilitating.

    The idea of the thermal camera to measure pain sounds interesting, though it would not work on a polio limb, as mine has always run on the cold side.

    My concern is that there may be people who are suffering with statin poisoning without even realising – perhaps with a wrong diagnosis for something else – such as post-polio. I also talked to a man who had encountered another recognised statin side-effect – memory loss and confusion. I seriously wonder how many people have declined into apparent dementia and are still being dutifully fed their daily statin tablet by their carers!

    I agree with you that this is in part a political problem – conventional politicians have become far too close to big business in all its forms. We do need a political shakeup in Britain, and hopefully UKIP might just achieve that!

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