Robert Heaney, Ph.D., Professor of Medicine, Creighton University, and Jeffrey Blumberg, Ph.D., C.N.S., Director, Antioxidants Research Laboratory, Tufts University, USA
“Nutritional science has seemingly swallowed the rules of evidence-based medicine (EBM) whole, without either asking how well it might fit, or adapting it to the unique features of the nutrition context. However, EBM differs from evidence-based nutrition (EBN):
- medical interventions are designed to cure a disease not produced by their absence, while nutrients prevent dysfunction that would result from their inadequate intake;
- drug effects are generally intended to be large and with limited scope of action (e.g., on a single enzyme or receptor), while nutrient effects are typically polyvalent in scope and, in effect size, are typically within the “noise” range of biological variability;
- drug effects tend to have a response varying in proportion to dose, while nutrient effects often have a useful response occurring only across a portion of the intake range;
- drug effects can be tested against a non-exposed (placebo) contrast group, whereas it is impossible and/or unethical to attempt a zero intake group for nutrients;
- and therapeutic drugs are intended to be efficacious within a relatively short term while the impact of nutrients on the reduction of risk of chronic disease may require decades to demonstrate – a difference with signiﬁcant implications for the feasibility of conducting pertinent randomized controlled trials (RCTs).
While drug interventions may show no relationship between a drug and a health benefit, essential nutrients must have some health benefit; otherwise they would not be defined as such. Thus the questions instead must be: What is the full spectrum of dysfunctions or diseases produced by low intake of a nutrient? And how high an intake is required to ensure optimal physiological function or reduced risk for disease across all body systems? The effects of nutrients on diseases can take decades to manifest as measurable outcomes, which vary by individual and organ system, etc. (1). If the problem is deficiency, as is frequently the case with micronutrients – unlike drugs – supplementing the diet of healthy people that already have sufficient intakes of the nutrient cannot be expected to deliver spectacular results. But that does not mean that the nutrients in question confer no benefit.
It is not ethical to use the RCT design to test if a low amount of a nutrient causes disease, because it would be inevitable that some of the subjects in the study would develop the disease. This is where observational studies greatly aid, as they can test (without intervening and causing harm) in a spectrum of subjects who are consuming low to high amounts of a nutrient and assess disease endpoints. Confidence in nutrient recommendations can be made at a lesser certainty than what is established for drugs (and nutrients with a high benefit:risk ratio may require less certainty of efficacy). Unlike for drugs where irrefutable proof of efficacy should be demanded, decisions for nutrient recommendations should be instead based on if the evidence shows an inadequate (or excessive) intake shows probable harm. Although nutrient toxicity is of certainly a concern, it generally is not to the same degree of drugs, which are usually more targeted and potent in their effects. This greater safety net allows for more aggressive recommendations based on a lesser certainty.
Meta-analyses that only use RCTs miss differing design features that can provide insight into variability in the physiologic reasons for heterogeneity. Considering the variables is crucial to using meta-analyses to exa-mine not only what the average effect of a nutrient is, but how much the effect can vary in different studies. It is likely that most reviews of nutrients will come to erroneous conclusions if they are not performed by individuals who are content experts in the relevant biology. Yet studies that are badly designed continue to be included in systematic reviews.
Although the limitations of applying a pharmaceutical-style model to foods are well known in the nutrition science community, regulators continue to regard RCTs as the gold standard of scientific evidence. To con-tinue to insist upon RCT data for validation of the health benefits of nutrients will guarantee not certainty but stagnation. Policy makers must now accept that intervention trials designed to test the efficacy of powerful drugs on sick people are not always suitable for determining the benefits of nutrients. If your doctor relied on RCTs to give you medical advice, he would not advise you to not smoke, to drink enough water and to use a parachute when jumping out of an airplane.
It is both appropriate and necessary to make recommendations in the absence of definitive proof. With nutri-ents, the question is always not ‘whether’ but ‘how much’? But the RCT is poorly suited to answer such ques-tions. Currently, there are still only a handful of validated biomarkers for disease risk that regulators will consider in nutrition research, such as blood cholesterol, blood sugar, blood pressure and bone density. Additional biomarkers for disease and wellness are urgently needed, intended to substitute for clinical end-points. The challenge is that nutrients act in pan- systematic ways that affect overarching processes. We need a more nuanced approach that honors multiple disciplines and embraces complexity.”
Based on: Heaney R. and Blumberg J. A New Paradigm of Evidence-based Nutrition: Moving Beyond Randomized Controlled Trials. Institute of Food Technologists: Wellness 2012 Conference. March 2012, Chicago, USA.