A scientific framework for foods vs. drugs:
the new paradigm of evidence-based nutrition
Andrew Shao, PhD
Chair, IADSA Scientific Council
June 19, 2017
Outline
• Definitions
• Food for health maintenance & promotion
• Evidence-based medicine for foods: If the shoe doesn’t fit?
• Studying health
• Evolution of nutrition
• Conclusions & closing thoughts
Definitions
• Food (“Functional food”): “…food that beneficially affects one or more target functions in the body, beyond adequate nutritional effects, in a way that is relevant to either an improved state of health and well-being and/or reduction of risk of disease. It is part of a normal food pattern” (European commission)
• Drug (medicine): “…articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals” (US FDA)
• Essential nutrient: “Any substance which a living organism must consume from the diet in order to support normal health, development and growth” (EFSA)
• Bioactive dietary substances: “…constituents in foods and dietary supplements , other than those needed to meet basic human nutritional needs, which are responsible for changes in health status” (Office of Dietary Supplements, US National Institutes of Health)
• Probiotics: …"live micro-organisms which, when administered in adequate amounts, confer a health benefit on the host” (World Health Organization)
• Omega-3 (EPA, DHA)
• Flavanols
• Carotenoids
• Chondroitin
• Probiotics
Nutrition: scientific framework
• Diet and nutrition play a critical role in health maintenance and promotion, reducing (or promoting) chronic disease risk
• What scientific framework should be applied, what amount and level of evidence is needed for broad-based public health recommendations?
– Health Claims
– Dietary Guidelines
– Dietary Reference Intakes
• Is the framework established for drugs appropriate for foods?
• In order to make timely, informed decisions, the framework should be commensurate with the risk-benefit of the category
Food is not medicine
• ““…let food be thy medicine and medicine be thy food”, a widespread phrase quoted by today’s scientists…this literary creation is not only a misquotation but it also leads to an essential misconception: in the Hippocratic medicine, even if food was closely linked to health and disease, the concept of food was not confused with that of medicine”
• “By attributing pharmacological properties to foods, authors are confusing both food and medicine”
Cardenas D, Clinical Nutrition ESPEN 2013(8);6:e260–e262
Food: For Health Promotion
The process of enabling people to increase control over, and to improve, their health. It moves beyond a focus on individual behavior towards a wide range of social and environmental interventions. – World Health Organization
http://www.who.int/topics/health_promotion/en/
Dietary Guidelines: A cornerstone of Health Promotion policy
Drugs vs. Nutrients vs. Bioactives
Shao & Heber 2011 Bioactive Food Components: Changing the Scientific Basis for Intake Recommendations
Probiotics recognized as food
Guidelines for the Evaluation of Probiotics in Food Report of a Joint FAO/WHO Working Group on Drafting Guidelines for the Evaluation of Probiotics in Food London Ontario, Canada April 30 and May 1, 2002
Hierarchy of evidence in “evidence-based medicine”
Randomized controlled
trials
Prospective cohort studies
Case-control studies
Case series
Case reports
Expert opinion
Animal research
In vitro research
Systematic reviews & meta-analyses
Misapplication of evidence-based medicine
• Designed to assess safety and efficacy of drug therapy (single, isolated substances)
• In many cases, not designed to address unique complexities and challenges presented by nutrients and other bioactive food components
• In absence of similar guidelines for nutrition, has been applied to nutrition and bioactive research for the purpose of informing policy decisions
“If the shoe doesn’t fit, must we change the foot?” – Gloria Steinem
• A drug-free state exists that can be contrasted with a drug-added state; not the case with nutrients (or microbiota).
• Nutrients are subject to the body’s homeostatic control and have threshold effects, i.e., some physiologic measure improves as intake rises up to a level of sufficiency, above which higher intakes produce no additional benefit.
• Nutrients don’t function in isolation and have beneficial effects on multiple tissues and organ systems; a focus on a single or “primary” outcome measure, which is favored by evidence-based medicine, is not practical.
J. Nutr. 2008;138 1591-1595
Looking for the “magic bullet”
• Can a nutrient reverse the effects of life-long smoking?
“By analogy, when keys are missing, it is common to look for them under the lamppost where there is light rather than in the murky location where the keys were more likely dropped.” JAMA. 2009;302(19):2152-2153
Blumberg et al. Nutrition Reviews 2010 Vol. 68(8):478–484
“This may mean action at a level of certainty that is different from what would be needed in the evaluation of drug efficacy. Similarly, it is judged that the level of confidence needed in defining nutrient requirements or dietary recommendations to prevent disease can be different from that needed to make recommendations to treat disease…”
Risk-Benefit-Cost
Drugs
• High risk
• High benefit
• High cost
• Error concern – Type I (false positive)
Foods, nutrients and bioactive dietary substances
• Low risk
• Modest benefit
• Low cost
• Error concern – Type II (false negative)
• “Society does not need the same level of certainty concerning the effect of a low-risk nutrient or food as it does for a potentially higher-risk (and much more expensive) drug.”
“Clinically proven to..” “Improves” “Enhances” “Optimizes” “Decreases
risk of…”
“Supports” “Maintains”
“May support” “Animal study
shows…”
“In vitro study shows…”
Claim substantiation standard for food
RCT on product under intended
conditions of use
Systematic reviews of
RCTs/Epi studies on ingredient(s)
RCT study(s) on ingredient(s)
Epi study(s) on ingredient(s)
RCT(s)/Epi study(s) on related* ingredient(s) or conditions of use
Animal/in vitro data
*Different form, composition, dose, duration, target population, etc…than that used in product
Scie
ntific S
trength
Cost
of re
searc
h
Cla
im S
trength
Unclear
Likely
Probable
Established
Drug therapy
Certainty Continuum
Degrees of certainty
Studying health
• Health – what is it ?
– A state of complete physical, mental, social and spiritual well being and not merely the absence of disease – World Health Organization.
• Multi-dimensional
• Not strictly defined or limited
• Individually determined; perceived personally •
• Dynamic and time-dependent
The ability to adapt and self-manage in the face of social, physical and emotional challenges’ (Lancet 2009; Huber et al. 2011).
RCT Cost: Treatment vs. Prevention
Courtesy Dr. Josh Berman, NCCAM, NIH
Therapeutic (drug) trial Risk reduction (nutrient) trial
Those with disease at baseline
100% 0
Placebo administration 20% cured (80% still have disease)
20% acquire disease (80% do not acquire disease)
Intervention administration—if 25% effective
¼ of 80% (20%) cured; 60% still have disease
¼ of 20% (5%) do not acquire disease; 15% acquire disease
Desired statistical power a = 0.05, power = 0.8 a = 0.05, power = 0.8
Subjects required per group
64 714
Cost ($) 1.3 million >15 million
Courtesy Dr. Josh Berman, National Center for Complementary & Integrative Health (formerly NCCAM), NIH
• Health promotion/health maintenance exceedingly difficult to “prove”
• “…a gap exists between productive research and the effective implementation of these findings in the life of the consumer…there is also a strong and sustainable need to document markers and to assess the clinical significance of probiotics on human health…”
Miquel et al. Microbial Cell Factories (2015) 14:48
Biomarkers for studying disease may not be useful for health
• Surrogate endpoint: a biomarker that is intended to substitute for a clinical endpoint…expected to predict clinical benefit (or harm or lack of benefit or harm) based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence.
• Examples:
– Blood pressure for trials of several classes of antihypertensive drugs.
– LCL-C for statins
• Disease biomarkers are not suitable to define health
• Single biomarker at a particular time point will rarely give a good picture of health
National Academy Press, 2010
Measuring health promotion: Dynamic biomarkers for homeostatic adaptability
Gallager et al. Brit J Nutr 2010
Examples of “stress tests”
• Metabolic (OGT, lipid load)
• Physical exercise – VO2max
• Psychological (TST)
• Immune (bacterial, viral)
• Cognitive
Impact of probiotics on health
• Can probiotics improve host health?
• Composition of a ‘healthy microbiota’ remains unknown – “…the concept that a healthy microbiome can be defined by some
idealized community composed of defined populations of specific microbes is too simplistic in light of the consistent interindividual differences observed in many studies…”
Alou et al. Human Microbiome Journal 1 (2016) 3–11
Backhed et al. Cell Host & Microbe 2012(12):611
Probiotics & homeostasis
“…surprisingly few studies have addressed the ability of a probiotic to reinforce the colonizing microbiota’s ability to either resist perturbation to stressors (for example, antibiotics, poor diet, psychological stress) or quicken recovery from said stress…(this) could provide insights into the ability of probiotics to support host health through stabilizing the microbiota, rather than fundamentally changing its composition…”
Sanders BMC Medicine (2016) 14:82
• Nutrition has rapidly evolved from a simple, nutrient and reductionist
approach, to a complex systems approach
• ‘‘Nutrition science is defined as the study of food systems, foods and
drinks, and their nutrients and other constituents; and of their
interactions within and between all relevant biological, social and
environmental systems’’. The Giessen Declaration
Nutrition science has evolved
• To specify new principles, a new definition, and new dimensions and domains for nutrition science
• The Giessen Declaration • “…the human species has now moved from a time in history when the
science of nutrition, and food and nutrition policy, have been principally concerned with personal and population health and with the exploitation, production and consumption of food and associated resources, to…all relevant sciences…should be principally concerned with the cultivation, conservation and sustenance of human, living and physical resources all together; and so with the health of the biosphere’’. Public Health Nutrition: 8(6A), 673–694
From reductionism to holism
• In emphasizing specific nutrients, it fails to take into account the fact that food components interact in complex ways to give rise to emergent properties of diets that are not explicable at the level of individual chemical parts
Chronic disease, aging, health promotion
Overt nutrient deficiency
Simple Complex
Biology Biology
Environment
Genetics
Downey M. 2015. The putative 104 causes of obesity update. Downey Obes. Rep. http:// downeyobesityreport.com/2015/10/the-putative-104-causes-of-obesity-update
• “Nutrition is a field in which the need for interdisciplinarity is particularly pronounced, given the pervasive influence of nutrition on humans, from physiological to social, global, and planetary levels, and its extensive relationships with other domains including economics, politics, and environmental science”
The “ecology” of nutrition
Fontiers in Nutrition. Sept 2015, Vol 2(26)
Narrow recommendations
Nutrients
Foods
Deficiency disease
Broad recommendations
Dietary landscape
Dietary patterns
Nutrients
Red
uctio
nism
H
olism
Evolution from linking health benefits to specific nutrients at specific doses (similar to pharma), to understanding the broader landscape that impacts health
What is the “dietary landscape”?
Dietary landscape
Foods
Culture
Environment
Dietary patterns
Social/psychological factors
Home/Workplace/Sch
ool
Economy
Food policy
Closing thoughts
• Drugs and foods (including nutrients and dietary bioactive substances) have different definitions and require different scientific frameworks for evaluation
• The framework established for drugs (EBM) is inappropriate for foods – Drugs: single, isolated compounds for treatment
– Foods: complex mixtures for health maintenance and promotion
• The level of certainty needed for drug approval is not necessary for foods
• Nutrition science has evolved to be more holistic, further evidence that it does not fit in a drug paradigm