How to Design a Drug Trial

Recently I came across a trial involving the cholesterol-reducing drug ezetimibe, published on April 16 in Atherosclerosis. Ezetimibe works in a different way from statins (the most commonly prescribed cholesterol-reducing medication). Statins block cholesterols production in the liver, while ezetimibe blocks cholesterols absorption from the gut.When you add ezetimibe to a statin (theres a medication called Vytorin that includes both), you can surely get a stunning reduction in cholesterol numbers. The problem is, the effect drugs (or anything else) have on cholesterol is irrelevant; its the impact they have on health that counts.If you can fix this fact in your mind, you will be way ahead of many doctors and researchers in your thinking.Ezetimibe beautifully demonstrates why its important to focus on its impact on health rather than cholesterol since not one single study to date has shown it to improve clinical outcomes. In fact, as this study demonstrates, there is evidence that ezetimibe might actually worsen outcomes.Yes, thats right, we have a system that allows us doctors to dispense drugs that have not been proven to be beneficial and where the balance of evidence suggests they have the potential to cause harm.This is what happens when those we entrust to keep us safe buy into the cholesterol is king mentality that the drug companies push incessantly. My advice is not to buy into it.There simply isnt any truly good news about ezetimibe, and on a deep level, its manufacturers (Schering-Plough Corporation) must be disappointed and embarrassed by it. But that wont stop the research. In such a situation, all you can do is conduct more and more studies and hope something sticks.In the bad old days, negative studies with disappointing results for companies and their shareholders could be buried, which made things a lot easier.Now, there is much more pressure to publish negative results, as trials are generally registered prior to getting underway. So researchers and the drug companies who pay for t! hem have to get increasingly creative to ensure they get the result they want (or avoid getting the result they dont want).For example, Id like to discuss briefly another ezetimibe study that was published in the Lancet on June 8. The study subjects had varying degrees of kidney failure. About half of them were treated with simvastatin (a statin) and ezetimibe for an average of almost five years, while the rest got a placebo (inactive medication).The results showed that those taking the drugs had a 17 percent reduced risk of the primary endpoint. The primary endpoint, though, was made up of a ragbag of things including heart attack, fatal heart attack, ischemic stroke (stroke caused by vessel blockage), and stenting (the placing of a tube in an artery to keep it open).The more things you group together like this, the more likely you are to get a statistically significant result. Also, the primary endpoint excluded death from hemorrhagic stroke (stroke due to vessel bleeding), which is important since lower cholesterol is associated with an increased risk of this kind of stroke.Focusing on individual outcomes, we see that the treatment did not lead to a significant reduction in non-fatal heart attacks, fatal heart attacks, or overall risk of death. In other words, the treatment did not save lives.Lets look at the broad design of this study. Here, the active treatment was statin and ezetimibe. The comparison group took a placebo. How do we know from this study if ezetimibe contributed in any way to the unimpressive benefits seen? We dont. To know if ezetimibe added something, the study would need to have included a group taking a statin on its own.We have previous evidence that ezetimibe not only does not help when added to a statin, but also the outcomes can actually be worse.Of course, one way to prevent such embarrassments and dips in share price would be to design your trial in a way that stands no chance of detecting such things. I think the researchers responsible for this latest trial need to take note.! Dr. John Briffa is a London-based physician and author with an interest in nutrition and natural medicine. His website is DrBriffa.com