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