Transcript Council for Responsible Nutrition IADSA Scientific Forum 2009

Assessing the Effects of Nutrients in
Humans
Defining Evidence-Based
Nutrition
Council for Responsible Nutrition
IADSA Scientific Forum 2009, Moscow, Russia
Outline
I. Impact of chronic disease and role of nutrition
policy
II. Current standard for research and evaluating
evidence
–
“Evidence-Based Medicine”, EBM
III. Shortcomings of EBM for nutrition research
IV. Shifting the paradigm
–
“Evidence-Based Nutrition”, EBN
Council for Responsible Nutrition
IADSA Scientific Forum 2009, Moscow, Russia
Prevalence of Chronic Disease
Europe:
33 million with diabetes
USA:
>900,000 deaths from CVD
China:
>2 million with cancer
Americas:
33 million with diabetes
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Source:
World
Organization
Source: World
Health Organization
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CVD Economic Burden
Source: American Heart Association Circulation 2007;115;e69-e171
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Other Costly Conditions
• Diabetes
• Alzheimer’s
• Osteoporosis
• Macular degeneration
• Cancers
→All have a substantial impact on quality of life and
healthcare costs; all are linked to diet and nutrition
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Role of Nutrition
• Diet and nutrition play a critical role in reducing (or
promoting) chronic disease risk
• What amount and level of evidence is needed for
broad based public health recommendations?
– Health Claims
– Dietary Guidelines
– Dietary Reference Intakes
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Continuum of Scientific Evidence
Public health
recommendations
Strength and consistency of
scientific evidence
Scientific Consensus
Significant Scientific Agreement
Emerging Evidence
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Some evidence
• Not conclusive
• Limited and not conclusive
• Very limited and preliminary
evidence; little scientific evidence
to support
• Benefit is highly unlikely/uncertain
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The Proof for Prevention
“The evidence is not as robust as it needs to be to justify the
enormous efforts and costs that are associated with
preventive interventions. It is important to move beyond the
science of observation…
We are calling for papers on the topic of prevention with a
particular focus on interventions that address the efficacy or
effectiveness of interventions. Ideally, these papers should
focus on randomized controlled clinical trials, which are the
preferred method to assess efficacy.”
O’Malley and Greenland. Arch Intern Med 2006 Mar 13;166(5):486
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Hierarchy of Scientific Evidence
“Evidence Based Medicine”
RCT
Observational
studies
Animal models
In vitro models
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Evidence-Based Medicine
• Designed to assess safety and efficacy of drug
therapy
• Considers the randomized-controlled trial (RCT) to
be the “gold standard” of evidence
• In absence of similar guidelines for nutrition, has
been increasingly applied to nutrition research
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USFDA’s Process for Reviewing
the Scientific Evidence
“…when randomized, controlled intervention studies are consistent
in showing or not showing a substance/disease relationship, they
trump the findings of any number of observational studies…”
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Widely cited for the proposition that Beta-carotene does not reduce the risk of cancer
and actually can increase risk.
But this study was not designed to address that question!
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Health Claims: FDA’s approach
• “…numerous examples -- such as vitamin E and CVD, folate and
CVD, and beta-carotene and lung cancer -- where associations
identified in observational studies... However, when
randomized, controlled intervention studies were later
conducted to test these possible associations, the intervention
studies found no evidence to support the relationships…”*
• But these studies did NOT ask and answer the same questions,
so one cannot be used to confirm or refute the other!
*CFSAN/Office of Nutrition, Labeling and Dietary Supplements January 2009
Evidence-Based Review System for the Scientific Evaluation of Health Claims Guidance
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FDA Approved Health Claims
Dietary substance
Disease risk
Year approved
Calcium, Vitamin D
Osteoporosis
Dietary Lipids
Cancer
1993
Dietary Saturated Fat and Cholesterol
CHD
1993
Dietary Non-cariogenic Carbohydrate
Sweeteners
Dental caries
1996
Folic Acid
Neural Tube Defects
1996
Fruits and Vegetables
Cancer
1993
Fruits, Vegetables and Grain Products that
contain fiber
CHD
1993
Sodium
Hypertension
1993
Soluble Fiber from Certain Foods
CHD
1997
Soy Protein
CHD
1999
Stanols/Sterols
CHD
2000
Whole grain foods*
CHD, Cancer
2003
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Potassium*
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Hypertension,
Stroke
2000 Russia
1993, 2008
FDA-Authorized Qualified Health Claims
Claim
Year
Tomatoes and Prostate, Ovarian, Gastric, and Pancreatic Cancers
2005
Calcium and Colon/Rectal Cancer and Calcium and Colon/Rectal Polyps
2005
Green Tea and Risk of Breast Cancer and Prostate Cancer
2005
Selenium and Certain Cancers
2003
Antioxidant Vitamins and Risk of Certain Cancers
2003
Folic Acid, Vitamin B6, and Vitamin B12 and Vascular Disease
2001
Nuts and Coronary Heart Disease
2003
Omega-3 Fatty Acids and Reduced Risk of Coronary Heart Disease
2004
Phosphatidylserine and Cognitive Dysfunction and Dementia
2003
Chromium Picolinate and a Reduced Risk of Insulin Resistance, Type 2 Diabetes
2005
Calcium and Hypertension, Pregnancy-Induced Hypertension, and Preeclampsia
2005
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Claim
FDA Authorized Qualified Health Claims
Lycopene and Various Cancers
Calcium and Risk of Breast and Prostate Cancers
Green Tea and Risk of Various Cancers
Fiber and Colorectal Cancer
Lycopene and Various Cancers
Green Tea and Reduced Risk of Cardiovascular
Eggs with Enhanced Omega-3 Fatty Acid Content and Reduced Risk of Heart Disease and Sudden Fatal Heart
Attack
Vitamin E and Heart Disease
Green Tea and Reduced Risk of Cardiovascular Disease
Chromium Picolinate and a Reduced Risk of: Cardiovascular Disease
Xangold® Lutein Esters, Lutein, or Zeaxanthin and Reduced Risk of Age-related Macular Degeneration or
Cataract Formation
100 Percent Partially Hydrolyzed Whey Protein in Infant Formula and Reduced Risk of Food Allergy in Infants
Calcium and Kidney/Urinary Stones
Calcium and a Reduced Risk of Menstrual Disorders
Glucosamine
and/or
Chondroitin Sulfate
and a ReducedIADSA
Risk of:Scientific
Osteoarthritis
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Explanations for Denials
• Failure to establish causality
– Reliance on observational data
– Lack of quality RCTs
• Failure to demonstrate risk reduction
– Reliance solely on data from diseased populations
• Failure to properly characterize substance
• Reliance on biomarkers that are not validated
surrogate endpoints or modifiable risk factors for
disease
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EU: Claims & Food Labeling
Health
Claim
Legislation
Group 2
Article 13.1
Group 3
Article 13.5
Group 4
Article 14
Description
Claims that state, suggests
or imply a relationship
between a food category, a
food
or one of its constituents,
and health
Reduction of disease risk
claims and claims referring
to children’s development
and health
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Application
‘Generic’ generally
accepted claims; well
understood
Newly developed
scientific data/IPR
Full authorization
procedure (Articles
15, 16, 17 and 19)
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EFSA Guidance
• EFSA Scientific & Technical Guidance July 2007
– Guidance for the Preparation and Presentation of the
Application for Authorization of a Health Claim
– Does not provide insight into the how the data are
evaluated
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EFSA Article 14 Decisions to Date
• “The Panel concludes that the evidence provided is not sufficient
to establish a cause and effect relationship between the
consumption of X products® and the reduction of the risk of Y
disease or condition...”
• Nearly 40 petitions denied
• Approximately 12 approved
–
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–
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DHA and visual development
Ca, vit D and bone health
Protein and bone health
Xylitol in chewing gum and tooth decay
Phytosterols and cholesterol
ALA, LA and growth and development in children
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What do the results of recent trials mean?
Have these trials
actually answered
the right questions
using the right
approach?
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Calcium & Vitamin D: Effect on Fractures
WHI study
• > 36,000 PM women
• 400 IU + 1000 mg
Ca/d
• Poor compliance
• Supplement use in
placebo group!
Minimum doses - Ca
(1200 mg), vitamin D
(800 IU) per day
(above current AI)
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Tang et al. Lancet 2007; 370: 657–66
Implication of WHI
“The results of the WHI add further evidence that clear answers to
questions about the long term effects of diet on risks of cancers and
other major diseases may not be obtainable by large randomized
intervention trials, no matter how much money is spent conducting
them.”
- Harvard School of Public Health
www.hsph.harvard.edu/nutritionsource/low_fat.html
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J. Nutr. 2008;138 1591-1595
• A drug-free state exists that can be contrasted with a drug-added state;
not the case with nutrients.
• 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 RCTs, is not practical.
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Study Design and the Nutrient Threshold or
“Status”
Effect
Examples:
- WHI
- SELECT
- GAIT
Nutrient Dose
Courtesy Robert Heaney, MD, Creighton University
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Feasibility of RCTs
Am J Clin Nutr 2009;89(suppl):1488S–93S.
• The effect of exposure of the fetus in utero to methyl
donors (e.g. folate, B12, betaine, choline) on fetal
development or chronic disease risk of offspring
• Can this be addressed by RCTs?
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Cost of Prevention RCT
• Initially: No one [0%] has disease
• Placebo administration: 20% acquire disease
• Dietary Supplement administration:
25% effective
¼ of 20% [5%] do not acquire disease
15% acquire disease
• For a=0.05, power =0.8:
N=714 subjects per group
$15,000,000 +
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Courtesy Dr. Josh Berman, NCCAM, NIH
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Cost of Treatment RCT
• Initially: Everyone [100%] has disease
• Placebo treatment:
20% cure = 80% have disease
• Dietary Supplement treatment:
is 25% effective
¼ of 80% [20%] more patients are cured
60% have disease
• For a=0.05, power =0.8:
N=64 subjects per group
$1,300,000
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Courtesy Dr. Josh Berman, NCCAM, NIH
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“…nonpharmacological dietary prevention of prostate cancer is probably more complex
and may involve certain inconvenient truths... If it requires whole foods, extracts, or
dietary patterns, it may be necessary to give up the reductionist need to know which
molecule is most responsible and perhaps give up the notion of placebo controls as well.
If it requires starting exposure early in life and sustaining it for decades, it may mean
having to give up the idea of phase 3 trials altogether. This does not mean that whole food
or complex mixture studies cannot be sound and biologically based…it may be time to
critically examine the methods used to vet hypotheses for some phase 3 trials…”
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Defining
Evidence-Based Nutrition (EBN)
Where to go from here
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I: Redefine Expectations
• Paradigm must shift, expectations must be
redefined
• Move from “EBM” → “EBN”
• “Reductionist” approach for single, isolated
nutrients no longer appropriate
• Nutrient-nutrient interactions
• Ca, vit D, protein
• Folic acid, B12
• Antioxidant network
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Bioactive Substances?
Essential Nutrients
(e.g. vitamins, minerals,
amino acids, etc…)
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“Bioactives” –
nonessential or
conditionally essentials
(e.g. coenzyme Q10,
lutein, α-lpoic acid,
isoflavones, etc…)
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II: Degrees of Certainty
• Consider policy decisions based on the “certainty”
of the nutrient/diet-disease relationship
Unclear
Probable
Preponderance of
evidence
Drug therapy
Likely
Unequivocal
Certainty Continuum for Prevention
• Consider risk-cost-benefit
• Supplemental nutrients
• Low risk + low cost + modest benefit
• Type II error
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III: Develop Better Phase 3 Trials
• Greater utilization of biomarkers
• Nutrient exposure/status, at baseline and throughout
• Surrogate disease endpoints
• Consider more integrative approaches in study
design
• Combine nutrient intake with other lifestyle
approaches
• Include more global indices of health
• Employ composite or global measure of all
appropriate endpoints, i.e. a “total body” health benefit
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Adaptive Trials?
• Data are analyzed on an interim basis and
used to dictate the future course of the
trial
• Requires fewer patients to achieve
statistical significance
• Traditional trials focus on a cross section
of the general population, adaptive trials
could use biomarkers to identify
responders and nonresponders
• Vulnerable to unblinding and bias
• Logistically, very complex
Kuehn, B. M. JAMA. 2006;296(16):1955-1957
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Biomarkers-Surrogate Endpoints
• A biomarker 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*
• Disease-risk reduction research faces serious practical and
fiscal limitations
• The future of health claims depends substantially on the
establishment of more surrogate endpoints for chronic
disease
*Biomarkers Definition Working Group -1998
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Surrogate Endpoints Recognized by FDA
Chronic disease
Surrogate endpoint
Cardiovascular disease
LDL-C
Blood pressure
Colon cancer
Polyps
Osteoporosis
Bone mineral density,
fracture
Diabetes
Blood sugar/insulin
resistance
Cognitive decline
Dementia
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Surrogate Endpoints NOT Recognized
Chronic disease
Surrogate endpoint
Cardiovascular disease
Serum homocysteine,
triglycerides, HDL-C
Inflammatory factors, CRP, etc…
Osteoarthritis
Cartilage deterioration, Joint
space narrowing
Macular degeneration
Macular pigment optical density
Prostate cancer
Prostate specific antigen
Various chronic
diseases
Single nucleotide polymorphisms
(SNPs), other “omics”
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Institute of Medicine
• Committee on Qualification of Biomarkers as
Surrogate Endpoints in Chronic Disease Risk
• Convened at the request of FDA (specifically CFSAN)
• Objective is to provide FDA with scientific framework
needed to determine which biomarkers can be
considered validated surrogate endpoints for disease
• Committee meetings Jan. 12, April 6, 2009
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IV: Improve Risk Stratification
• Include nutrigenomic, proteomic and metabolomic
assessments
• Utilize single-nucleotide polymorphisms (SNPs) to identify
responders and nonresponders
• Will help design targeted trials with higher statistical
efficiency and more favorable risk-to-benefit ratios
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V: Beware the Meta-analysis
• Over-reliance on MA restricted to RCTs that fail to
account for reasons for heterogeneity
• Has evolved in to a synthetic tool
• Means of aggregating different studies to obtain better
estimate of overall effect
• Should be utilized as an analytic tool
• Delineation of why studies differ in magnitude and direction
of effects
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Thank you!
Andrew Shao, Ph.D.
Phone: (202) 204-7660
Fax: (202) 204-7701
[email protected]
www.crnusa.org
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