Earlier this week the Daily Mail published my feature on side-effects and how patients aren’t properly warned about them. Antidepressants, for instance, can cause compulsive heavy drinking but you wouldn’t know it from the drug information leaflet.
The article is about campaigning psychiatrist Dr David Healy, who believes patients need a more truthful account of the side effects they risk. It describes his new website – Rxisk.org – that makes it easier to report side-effects and provides a forum where you can swap experiences with other pill users.
Information about side effects is often poor because it gets hidden by the companies running the trials. A campaign by doctors and journals is now well under way to force drug companies to be more transparent.
Turning garbage into gold
But that’s not enough, according to Healy. He believes there are serious problems with the randomised controlled trial (RCT), the so-called gold standard of evidence based medicine, used to test treatments and decide which ones should be licenced.
Rather than distinguishing safe and effective medical treatments from ones that are dangerous and/or useless, the results from RCTs are frequently misleading and wrong. The RCT, he says, is a processor for turning garbage data into drug company gold.
At first sight his critique appears ridiculous. It is a full-frontal challenge to the whole idea of evidence based medicine. You have to have a way of telling if a drug works and is safe and the RCT has been used for years – since the 1960’s in fact – when it was introduced as a response to the thalidomide disaster.
It works by dividing patients randomly into two groups; one lot gets the drug, the other an inert placebo pill. A few months later the results reveal which group benefited more. Two positive RCTs are needed to get a licence to market a drug.
A serious barrier to treating chronic disease
Healy’s case against RCT’s is not based on bare-faced fiddling of results by the drugs companies, although he’s often exposed it. Even if all trials were squeaky clean they would still be a serious barrier to developing really effective ways of tackling the various lifestyle diseases that are threatening to cripple Western health services.
Take the rule that you only need two RCT’s to get a licence. What about if you also have three negative ones where the drug came out as no better than a placebo? At the moment they simply don’t count. This has everything to do with bureaucratic rules and nothing with scientific rigour. Its an arbitrary rule that deprives doctors and patients of valuable information about what the drug does or, just as importantly, doesn’t do.
But there is more fundamental problem. Properly conducted RCTs are supposed to tell you if a drug is effective. But what does “effective” mean? The poster boy for the industry is the antibiotic – a drug that rapidly cures the problem in the great majority of people who take it.
Most drugs aren’t like antibiotics
That would be a good definition of “effective” but that’s not what most drugs that come onto the market today do. (Ironically antibiotics worked so well when they were initially developed they didn’t require an RCT to show effectiveness. Today the fact they are so effective means companies have stopped making them; a quick cure is not profitable enough)
The RCT system finds many drugs effective not because they cure anything but because they change some marker or risk factor for disease, such as reducing your cholesterol level or the size of your tumour. But often changing these markers has no effect on long term outcome. For instance Ezetimibe is very effective at lowering cholesterol; however there is no evidence it has any effect on your chances of developing heart disease.
It’s assumed that if a drug has been found to be effective in an RCT, it will be just as effective when it is handed out in the doctor’s surgery. NICE, for example, uses data from RCTs to decide if a drug is cost effective. RCTs are also used to estimate safety when a drug becomes widely used. The list of side effects set out in the Patient Information Leaflet contains those reported in trials.
Dangers of drugs in the real world
But the few attempts to test these assumptions show them to be false. An RCT is a highly specialised set up: the patients are carefully selected. Usually they are younger and healthier than the people who will actually be taking drug. They will only have one thing wrong with them and only be taking that one drug. People in the real world will be older and very likely have two or three conditions for which they are also taking five or more drugs.
A study comparing the cost effectiveness of a drug based on the results from RCT trials with results in a clinic found they were about five times less effective. This not only raises the issue of effectiveness – many widely used drugs only work for 25 to 40 per cent of patients according to RCTs – but it also puts a big question mark over safety.
Just as effectiveness drops outside the rarefied world of RCTs, the number and variety of harmful side-effects inevitably shoots up. But official figures on how safe and effective a drugs is come from the RCT data. In the real world that balance can have dramatically changed.
Letting in dangerous and incompetent characters
Ultimately though the problem is that an RCT is a handy tool, especially for finding out what doesn’t work, that has been elevated way above its pay grade. It’s not up to the job of being the gate keeper for evidence based medicine.
It has let in all sorts of dangerous and incompetent characters and it’s a totally inappropriate tool for assessing treatments that are much more sophisticated, individually targeted and flexible than 5 or 10 mg of a drug.
Even worse, the RCT ignores how medicine really works by undermining doctors’ clinical judgements. The RCT system we have operates on the unspoken assumption that drugs found to be effective automatically fall into the Magic Bullet class. Just like antibiotics, they target the problem and work whatever the situation a patient is in.
But as Healy points out, most drugs, such as painkillers, tranquillisers or anti-inflammatories like aspirin, work within a “therapeutic relationship”. They aren’t cures but they can help, along with a range of other things, depending on all sorts of factors in the patient’s life, from genes to family relationships.
Delusion of the magic bullet
But there is a strong tendency for drugs passed by the RCT magic bullet model, to be seen as automatically effective and appropriate for everyone. They are fire-and-forget treatments to be used according to guidelines.
In the kind of personalised medicine Healy and many other doctors are campaigning for, a clinician would say something like: “This treatment has an effect which may be beneficial for you, taking into account everything else going on in your life.” The RCT magic bullet approach says: “This treatment has been proved to be effective and so it’s appropriate for you.”
But the one-size-fits-all approach is going to become increasingly irrelevant in the face of an explosion of genetic information pinpointing detailed individual differences and the ways genes and environment interact to affect health. It’s also not an effective way of assessing the preventative and tailored life-style changes needed to deal with the epidemic of chronic metabolic disorders. We need to come off the gold standard.