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Clinical trials - gold standard or white elephant?

25-Jun-2007

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Randomised clinical trials are the ultimate. Forget what the observational studies tell us, if the RCT gives us an answer it must be the final word, right? Wrong.

The value of such trials for the food industry is undeniable, but too often nutrients are pulled out of context, following the same methodology as used for the testing of drugs. But let's not forget that by following the drug model we are supplementing the diet with one or two nutrients, each at a single dose, for a set period of time. Can a time-constrained randomised trial really capture a lifetime of consumption with respect to chronic disease? Randomised clinical trials work by randomly assigning a group of volunteers to receive an active compound, be it a drug or nutrient(s), or a non-active comparison, be it an inactive form of the active compound or a placebo. Observational studies, as the name suggests, observe a population and relate dietary intakes of food and nutrients to the occurrence of disease. We need to consider the science as a whole and not blinker ourselves with results of one big clinical trial, regardless of how much money it costs and what universities were involved. For food items that do not normally form part of the usual food chain, randomised clinical trials are the best of the best because such compounds can be tested and retested successfully. Phytosterols, probiotics, or botanical supplements, for example, fit into this category. Indeed, clinical trials on phytosterols have shown time and again that daily consumption of 1.5 to 3 grams of phytosterols/-stanols can reduce total cholesterol levels by eight to 17 per cent, representing a significant reduction in the risk of cardiovascular disease. Studies looking at how these results transfer into real free-living populations have backed up the clinical trials, showing a stabilisation of cholesterol levels in certain populations. So we know the benefit of clinical trials. But when we start using this approach for vitamins, minerals, antioxidants and other nutrients, we come a little unstuck. Some may say that I'm over-reacting, but let's just look at the report published in the New Scientist magazine that slammed antioxidant supplements as myth. Despite a vast body of observational/ epidemiological studies linking an increased dietary intake of antioxidants from fruits and vegetables to reduced risks of a range of disease, including cancer, cardiovascular disease and diabetes, when such antioxidants have been extracted and put into supplements, the results, according to RCTs, do not produce the same benefits and may even be harmful. So the author of the article, Dr. Lisa Melton from the London-based registered charity, the Novartis Foundation, concluded that antioxidant supplements are too good to be true. Is this really the answer or is it due to poor study design? Would a two-year trial of vitamin E, let's say, really produce a reduction in the risk of a chronic disease? To illustrate this point further, we only need to go back to last year's Women's Health Initiative (WHI) trial that followed 18,176 post-menopausal women taking calcium (1000 mg) and vitamin D (400 IU) supplements. A similar population (N=18,106) was given a placebo. The subjects were followed for about seven years and the researchers reported that the supplements 'had no effect' on the risk of colorectal cancer. None of the women had the cancer at the start of the study and colorectal cancer has a long latency period of 10 to 20 years, which begs the question - could we really have expected to see an effect? We also need to remember that nutrients often work in synergy with one another and exert effects on multiple body tissues, unlike pharmaceuticals. Additionally, many randomised clinical trials look at the effect of nutrients in diseased populations. Surely the damage of a lifetime's poor nutrition has already been done. When we obtain negative or null results from such trials, should we really be surprised? The power of nutrients is in the prevention, not cure, of disease. So what should we do? I don't pretend to have any answers. These are for ladies and gentlemen with infinitely bigger brains than me. Realistically, there are no viable alternatives out there at present. Randomisation is the best way of limiting bias that creeps into every study, and controlling, specifically with placebo, is the best way to make comparisons. For those times where randomised trials clearly aren't the best option, then we probably need to look at the observational studies and mechanistic studies in greater depth, and place more value on them. The research community as a whole must work together to re-evaluate how to get the most from research into nutrition. Lots of different types of studies are out there. Let's make the most of what we already have. Stephen Daniells is the Food Science Reporter for NutraIngredients.com and FoodNavigator.com. He has a PhD in Chemistry from Queen's University Belfast and has worked in research in the Netherlands and France. If you would like to comment on this article please contact stephen.daniells'at'decisionnews.com Readers' comments Thank you for publishing this sanity check. We are way out of line with where and how our research is currently conducted. Especially with epidemiology, the results become ever increasingly a matter of deciding ahead of time what outcome is desired and then working the tests to prove it. I have lost faith in today's scientific "evidence." - Susan R. Feldman, President, Susan Feldman Consulting LLC., Alexandria, VA. USA Just read your article on the limited that view clinical trials produce on the effectiveness of vitamins, minerals, etc. and couldn't agree more with what you are saying. Just wanted to let you know that I enjoyed your article and I think the points you raise deserve serious attention by those who conduct such trials and offer opinions to the public as a result.


- Terry, Australia