Are clinical trials relevant?

I happened to read two things on the same day. One was some post on social media that said Remdesivir is not effective. I don’t believe on such posts immediately so I looked for the original paper. It was a Lancet paper describing a multi centre clinical trial of Remdesivir which found no beneficial effect on Covid-19 patients. Within a few hours I came across a newspaper carrying a two column news with a picture of people demonstrating on streets demanding Remdesivir be made available. The background is that Remdesivir has been among the costliest drugs for the treatment of Covid. It’s being sold in black for tens of thousands of rupees per dose. People want to buy it desperately, obviously because their physicians prescribed.

I then looked for more published clinical trials of Remdesivir to find that two more peer reviewed publications had said that there was no effect, and two said there was some effect. It’s not new that different clinical trials have somewhat different results. This is possible by chance alone plus there are subtle differences in the trial design, randomization protocols used, patient groups, the locally prevalent genotype of the virus and so on. Such differences are common when the effects are marginal. In such cases factors like conflicts of interest, conformity bias, publication bias suddenly become extremely important. For any drug that is extremely effective, different trials may differ slightly in the magnitude of the effect, but all are unanimous about there being a significant effect. For such cases conflicts of interest and biases do not interfere much. Anything that is really effective gets unanimous support of trials. Anything that does not have consistent support across studies, has doubtful and at the most edge effects. Putting all the trials together, it is clear that Remdesivir does not make a convincing case, at the most it may have marginal benefits.

So why are people paying such a high price for a drug whose effects are doubtful? A simple behavioural reason is that when there is no good choice, people go for the best among the bad choices. The meaning of ‘best’ here is not a scientifically tested ‘best’, it is the one which is marketed most aggressively or most tactfully. I was not surprised when I realized what is happening with Remdesivir, because I have seen the same thing has been happening with diabetes (type 2) drugs.

No clinical trial has shown that normalizing blood sugar with any drug can arrest diabetic complications. Trials like UKPDS and ADVANCE showed some marginal benefits of treatment. On the other hand, trials like ACCORD and NICE sugar trial showed that mortality is higher in the carefully sugar controlled group as compared to the moderately controlled group. Further there were many obvious flaws in the study design of the trials that showed marginal positive effects. For example, UKPDS, which is said to be so far the most successful trial to claim some positive effects,  did not have any placebo control group. In a disease like diabetes, there are two levels of possible placebo effects. A placebo effect means getting better just by the belief or feeling of getting better. One is the feeling that I am being treated. This can be controlled easily by having a control group with blank pills. The other level is the feeling that “Oh, my sugar is normal now!” Some positive physiological effects are possible because of this feeling alone. To control for this second level placebo, one needs to have a group which is not treated with hypoglycemic drugs but who are made to believe that their blood sugar is normalized. Such a placebo control has never been kept by any of the clinical trials. So the chance that the marginal positive effects that a trial showed are only because of this feeling, is never eliminated. In short, there is no scientifically sound proof that normalizing sugar has any positive effect on the pathophysiology of diabetic complications. And still, all antidiabetic medicine focuses primarily on reducing blood sugar. All these perfectly useless drugs have an annual turnover in hundreds of billions.

This means that the actual results of clinical trials have no bearing on practicing medicine. This has been demonstrated by not one but several examples. An entirely different set of principles operates in the drug market. Patients and doctors are equally gullible. There is no doubt that some medicines have been really effective and they have sound and robust science support. But for diseases where there is currently no real effective medicine, everyone is being fooled by the best of the bad drugs. If there is no real solution as of now, will you go for something that doesn’t work? Surprisingly the answer is ‘yes’ for most people. Rather than facing the reality that nothing works, people will try anything including witchcraft, magical, spiritual healing practices. We can’t blame them because many of the mainstream medicine practices are not different from witchcraft. They are there not because of their efficiency, proven in clinical trials. They are there because nothing else works, so why not try this? When there is no real cure, you still have to give something that doesn’t work.

And that actually works!! Not for curing any disease, but for the feeling of having done something, and of course for making money.

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