A scientific framework for foods vs. drugs: the new paradigm of evidence-based nutrition

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1 A scientific framework for foods vs. drugs: the new paradigm of evidence-based nutrition Andrew Shao, PhD Chair, IADSA Scientific Council June 19, 2017

2 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

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

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

3 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,

4 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

5 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

6 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

7 Dietary Guidelines: A cornerstone of Health Promotion policy

8 Drugs vs. Nutrients vs. Bioactives Shao & Heber 2011 Bioactive Food Components: Changing the Scientific Basis for Intake Recommendations

Working Group on Drafting Guidelines for the Evaluation of

9 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

10 Hierarchy of evidence in evidence-based medicine Systematic reviews & meta-analyses Randomized controlled trials Prospective cohort studies Case-control studies Case series Case reports Expert opinion Animal research In vitro research

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

11 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

12 J. Nutr. 2008; 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.

13 Looking for the magic bullet Can a nutrient reverse the effects of life-long smoking?

14 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):

15 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 Blumberg et al. Nutrition Reviews 2010 Vol. 68(8):

nutrients and bioactive dietary substances Low risk

16 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)

17 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.

18 Scientific Strength Cost of research 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) Clinically proven to.. Improves Enhances Optimizes Decreases risk of Supports Maintains Claim Strength RCT(s)/Epi study(s) on related* ingredient(s) or conditions of use May support Animal study shows Animal/in vitro data In vitro study shows *Different form, composition, dose, duration, target population, etc than that used in product

19 Degrees of certainty Drug therapy Probable Established Likely Unclear Certainty Continuum

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.

20 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).

21 RCT Cost: Treatment vs. Prevention Health promotion/health maintenance exceedingly difficult to prove Those with disease at baseline Placebo administration Intervention administration if 25% effective Therapeutic (drug) trial 100% 0 20% cured (80% still have disease) ¼ of 80% (20%) cured; 60% still have disease Risk reduction (nutrient) trial 20% acquire disease (80% do not acquire 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 Cost ($) 1.3 million Courtesy >15 Dr. million Josh Berman, NCCAM, NIH Courtesy Dr. Josh Berman, National Center for Complementary & Integrative Health (formerly NCCAM), NIH

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

22 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

23 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

24 Gallager et al. Brit J Nutr 2010 Measuring health promotion: Dynamic biomarkers for homeostatic adaptability

25 Examples of stress tests Metabolic (OGT, lipid load) Physical exercise VO2max Psychological (TST) Immune (bacterial, viral) Cognitive

26 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 Backhed et al. Cell Host & Microbe 2012(12):611 Alou et al. Human Microbiome Journal 1 (2016) 3 11

27 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 science has evolved 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

28 Nutrition science has evolved 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

29 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),

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

30 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 Simple Environment Complex Overt nutrient deficiency Chronic disease, aging, health promotion Biology Biology Genetics Downey M The putative 104 causes of obesity update. Downey Obes. Rep. downeyobesityreport.com/2015/10/the-putative-104-causes-of-obesity-update

31 The ecology of nutrition Fontiers in Nutrition. Sept 2015, Vol 2(26) 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

32 Evolution from linking health benefits to specific nutrients at specific doses (similar to pharma), to understanding the broader landscape that impacts health Foods Deficiency disease Nutrients Narrow recommendations Dietary patterns Nutrients Dietary landscape Reductionism Holism Broad recommendations

33 What is the dietary landscape? Foods Food policy Culture Economy Dietary landscape Environment Home/Wor kplace/sch ool Social/psychologi cal factors Dietary patterns

34 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

II. History and importance of defining Healthy : Government/regulatory science perspective

II. History and importance of defining Healthy : Government/regulatory science perspective Barbara Schneeman, Ph.D. Professor Emerita of Nutrition University of California, Davis Main Question What are