Pharmaceutical Trials: Can We Trust Them?

The majority of doctors only accept treatments that have been proved to work in double-blind trials. In many ways this is a sensible policy for it is vital to know whether a treatment genuinely works or whether it is just a placebo.

The first medical trial was done by James Lind in 1747. He tested 12 sailors with scurvy with oranges and lemons and found it cured the disease. In fact, citrus fruits had been used by seafarers in the previous 200 years to ward off scurvy but its effectiveness was disputed by the medical profession. Only after the trial were citrus fruits accepted as a cure for scurvy. It was a defining moment in medical science.

         Today we use double-blind trials. In these, great lengths are taken to remove bias. Not only does the patient not know if he is taking a genuine treatment or a placebo but neither does the doctor. This, surely, should guarantee that the conclusions of the trial are beyond question.

         It would not be an overstatement to say that the whole edifice of modern medicine depends on the reliability of these double blind trials.

           So, if these trials are so fundamental to medical science, can we put all our trust in them? The answer may surprise you.

 It turns out that there are major flaws in these trials and these flaws are so widespread and so serious that they bring the whole basis of evidence-based medicine into question. 

Flaw One

The first flaw is that if only trials with a positive outcome are published and the negative trials are binned then bias becomes inevitable and serious. The way the system works is a drug company needs to produce two positive trials to have a drug approved. It matters not if there are ninety-eight negative trials on the same drug.

You might ask could this really happen? Well, it can and it has. Take the case of the anti-depressive drug, Seroxat. The drug company did three trials on teenagers with depression. One trial showed no difference between Seroxat and placebo, one trial showed the placebo was more effective than the drug and the third was inconclusive. However a subgroup in the third trial showed some benefit. What got published? Only the results of the subgroup in the third trial and the drug was claimed to be an effective treatment for teenage depression, when, in reality, the opposite was true.

This is known as publication bias and the results of 40% of drug trials performed are never released. And that’s not all: many more trials only have part of the data released.

Flaw Two

         In a similar way it is possible to extol the good points of a drug and bury the adverse ones.

         The VIGOR trial in 2000 had shown that there was very high risk of cardiovascular events with the drug, Vioxx. It found an excess of seven to eleven cardiovascular events for every hundred patients taking the drug (this is very high) in comparison to those taking an older anti-inflammatory drug called naproxen. When the numbers were crunched, Vioxx had caused five times as many myocardial infarcts as naproxen (which can also cause cardiovascular events). However this was not how the drug was marketed: it was sold as a drug that caused less gastro-intestinal problems (a common adverse effect with anti-inflammatory drugs).  Doctors were told of the advantages but not about the risk. It would be another four years before it was taken off the market and during that time it was estimated that it cost the lives of 60,000 patients.

Flaw Three

The average cost of a randomised placebo controlled trial is seven million dollars (one study of a cholesterol drug cost £35 million). The expense of this type of trial virtually excludes every non-pharmaceutical treatment. This means that only pharmaceuticals can ever be evaluated as only pharmaceutical companies can afford them.

This one fact massively skews medicine. It skews it towards a single mode of treatment and, worse still, excludes effective remedies not in this category. Lind would have never been able to test oranges and lemons and would never have found a cure for scurvy.

It skews it towards a form of treatment that has proved largely ineffective. Fifty years experience has shown pharmaceutical drugs to be a very blunt instrument for combating chronic diseases. It also skews it towards a hugely expensive form of treatment.

Unfortunately these are not the only problems with the double-blind trail. These trials have increasingly come under the scrutiny for all the wrong reasons.

 I have found that most doctors accept the results of these trials at face value. But one group of people are less easy to fool. These are the editors of medical journals and they have been raising the alarm for some time.

 In 2001 a joint statement by editors of the twelve leading medical journals stated that clinical trials were being used primarily for marketing. They said that this made a mockery of clinical investigation and that this was a misuse of a powerful tool. They noted medical scientists working on corporate-based research often had little or no input into trial design, no access to raw data and limited participation in data interpretation. They were telling us, in no uncertain terms, that these trials were more spin than science.

This led to a tightening up of the regulations in 2005 but in reality little changed.

In fact, they may have got worse. Editors of both the Lancet and New England Journal were recorded in conversation. Lancet Editor in Chief Richard Horton was heard saying, Now we are not going to be able to, basically, if this continues, publish any more clinical research data because the pharmaceutical companies are so financially powerful today, and are able to use such methodologies, as to have us accept papers which are apparently methodologically perfect, but which, in reality, manage to conclude what they want them to conclude.

By various means, pharmaceutical companies are able to override the evidence and unscrupulously market drugs with limited and sometimes zero benefits. These days, the company write up the results, not the scientists who conduct the trials.

You might ask: where are the regulators? Surely they would ensure fair play. This is unfortunately not the case. In the USA 40% of the wages of the FDA are paid by the pharmaceutical companies and in the UK it is 100%.

Perhaps because of this, malpractice is widespread and according to Public Citizen, between 1991 and 2017 there have been 412 settlements costing pharmaceutical companies $38.6 billion in criminal and civil penalties. 

John Ioannidis, Professor of Medicine and Statistics at Stanford University is an expert in this area and one of the world’s most influential scientists. He puts it this way: “the greater the financial interest in a given field the greater the likelihood that the research findings are false”. Worryingly he found 70% of health professionals fail tests on understanding evidence-based medicine.

 Sadly these trials, which initially promised so much, have degenerated into a scam of immense sophistication and sometimes outright fraud. They now have a stranglehold over medicine. The result:  the prescribing of more and more drugs, many of doubtful value.

         Since 2005 the number of prescriptions has tripled in the UK with no discernible benefit. In fact, life expectancy has started to decline since 2015.

         This prescribing bonanza is good for the pharmaceutical companies but tragic for patients who are now taking more drugs than ever before. It is also tragic for doctors who can no longer be sure if a drug genuinely works or not and are faced with ever more complex prescribing strategies and decreasing job satisfaction.

         For myself, I still strongly believe in the science of medicine and the underlying principles behind these double blind trials. However, I have long ceased to have any confidence in the results coming out of these trials as they have likely been spun and massaged to get the results the company require. Sadly, these trials have been hijacked for commercial gain and this is undermining the very building blocks upon which the science of medicine ultimately depends.