Nutrition Related Regulatory Nutrition Related Regulatory IssuesIssues

Nutrition Related Regulatory Nutrition Related Regulatory IssuesIssues

Kathleen Ellwood, Ph.D.Director, Division of Nutrition Programs

and LabelingOffice of Nutritional Products, Labeling,

and Dietary Supplements

Topics To Be CoveredTopics To Be Covered

• Fortification Policy• Biotechnology Labeling Guidance• Health Claims

Fortification PolicyFortification Policy

• Established in 1980• A uniform set of principles as a model for the

rational addition of nutrients to foods• Lists the 20 vitamins/minerals and ptn for which

there were established U.S. RDAs in 1980; appropriate fortification levels based on a nutrient density

Fortification Policy – con’t.Fortification Policy – con’t.

Addition of nutrients to foods can:• be an effective way to maintain and improve

overall nutritional quality of the food supply• create nutrient imbalances in the food supply• contribute to deceptive or misleading claims for

certain foods

Fortification Policy – con’t.Fortification Policy – con’t.

FDA does not consider it appropriate to fortify:• fresh produce;• meat, poultry, or fish;• sugars; or• “snack foods such as candies or carbonated

beverages.”

Biotechnology LabelingGuidance

Biotechnology LabelingGuidance

Voluntary Labeling

Indicating Whether Foods Have or Have Not Been Developed Using Bioengineering

Labeling of Bioengineered Foods

Labeling of Bioengineered Foods

• Food must be labeled when there is a significant change in the food: • nutritional;

• compositional;

• change in conditions of use; or

• when an allergenic component has been introduced in a food where it does not naturally occur.

FDA Actions FDA Actions

Held three public meetings in 1999

Conducted focus group studies

Developed draft guidance in

January, 2001

Biotechnology Draft GuidanceBiotechnology Draft Guidance

• Does not require special labeling of all bioengineered foods based on production method

• Restates agency’s policy regarding when special labeling is required for bioengineered foods

• On web at: http://www.cfsan.fda.gov/~dms/biolabgu.html

What It Takes To Get A Health Claim

Evidence-Based Ranking SystemEvidence-Based Ranking System

The review of the evidence for SSA health claims and qualified health claims is the same review.

Reviewing the Evidence 1999 and 2003

Reviewing the Evidence 1999 and 2003

Define substance/disease relationship

Identify relevant studies Classify studies Rate studies for quality Rate for strength of body of

evidence: quantity, consistency, relevance

Report “rank”

Substance/Disease RelationshipSubstance/Disease Relationship

Causal relationship between a substance and a disease or health related condition for the general U.S. population or subpopulation:

• Substance – food or food component

• Disease – damage to an organ, structure or system of the body such that it does not function properly (e.g. CHD), or a state of health leading to dysfunctioning (e.g. hypertension)

SSA and Qualified Health ClaimsSSA and Qualified Health Claims

Health Related Condition:• A condition so equivalent to the disease as to be

indistinguishable from the disease (e.g. hypertension), or

• A validated modifiable risk factor for disease (e.g. LDL cholesterol)

56 Fed Reg 2478 at 2481, Jan 6, 1993.

Relationships Between Diet and Disease

Or Health Related Conditions

Relationships Between Diet and Disease

Or Health Related Conditions

ValidatedModifiable

Risk Factors

Disease/Health Related

Condition

DiseaseSymptomsand Signs

Drugs21 USC 321 (g)(1)(B)

Health Claim21 USC 343(r)(5)(D)

Substance

Diseases and Validated Modifiable Risk FactorsDiseases and Validated Modifiable Risk Factors

CHD Total/LDL cholesterol

Cancer Colorectal/polyps

Diabetes Blood sugar levels

Osteoporosis Bone mineral density

Dementia Mild cognitive impairment

Identify Relevant StudiesIdentify Relevant Studies

• Studies involving healthy humans

• Studies that measure validated, modifiable risk factors

• Studies that measure reduced risk of disease or health related condition

Classify StudiesClassify Studies

• Intervention studies – “ Gold standard” -- Measured modifiable risk factor, i.e. LDL-

cholesterol soy protein and CHDwalnuts and CHD

-- Measured incidence of onset of diseaseomega-3 fatty acid and CHD fiber-containing grain products, fruit and

vegetables and cancer

Classify Studies – con’t.Classify Studies – con’t.

• Observational studies – less reliable-- measurement of substance-- confounders of disease (other nutrients)

• Prospective cohort

• Case-control

• Cross-sectional – least reliable

Rate Studies for QualityRate Studies for Quality

• Study design

• Data collection

• Inclusion and exclusion of study subjects

• Statistical methods/analysis

+ (good)

(moderate)

(poor)

Rate for Strength of the EvidenceRate for Strength of the Evidence

• Type of studies

• Quality

• Quantity of studies and sample size

• Consistency of findings

• Relevance to general population or target subgroup

Report “Rank”Report “Rank”

Significant Scientific Agreement

Strong, high quality, relevant and consistent body of evidence. Conclusions not likely to be reversed with new data (1999 and 2003)

High Level of Comfort = A

Report “Rank”Report “Rank”

Qualified Health Claims

• Moderate/good level of comfort (B)

• Low level of comfort (C)

• Extremely low level of comfort (D)

Qualifying LanguageQualifying Language

Intended to qualify the level of credible scientific evidence for a substance-disease (risk-reduction) relationship in the general population.

But Not Intended To Qualify The…• Extrapolation of treatment/mitigation data (drugs) to

risk reduction (nutrients).• Lack of a validated, modifiable risk factor which

serves as the link between a substance and disease risk reduction.

• Fact that evidence on disease risk reduction is only observed in animals.

Selenium and CancerSelenium and Cancer

Selenium and CancerIntervention Studies

Selenium and CancerIntervention Studies

• Clark et al., 1996 (Nutritional Prevention of Cancer Trial) – U.S. No effect on the primary end-point (non-melanoma skin cancer), reduced risk of total, prostate, lung and colorectal cancer

• Duffield-Lillico et al., 2002;• Reid et al., 2002 – post-hoc analysis, 7.9 yr follow-up,

reduced risk of total and prostate cancer; no longer with lung and colorectal; especially for males with low plasma selenium levels

• Yu et al., 1991 – reduced rate of liver cancer in malnourished Chinese

• Blot et al., 1993 (Linxian Trial) – lower stomach cancer mortality in malnourished Chinese

Selenium and CancerIntervention Studies – con’t.

Selenium and CancerIntervention Studies – con’t.

Multi-nutrient supplement provided - Not able to evaluate the effect of Selenium per se• Blot et al., 1993, 1995 - China

• Li et al., 1993 - China

• Prasad et al., 1995 - India

• Bonelli et al., 1998 - Italy

Selenium and CancerObservational StudiesSelenium and CancerObservational Studies

36 Studies

16 prospective cohort studies,

3 retrospective case-control studies,

17 ecological and cross-sectional

½ supported an association for total cancers½ did not support an association for total cancers

Observational studies showed the greatest benefit with prostate cancer and no association of Se intake and

breast cancer.

Qualified Health ClaimQualified Health Claim

• Nutritional Prevention of Cancer Trial, showed a benefit in males with low plasma selenium levels with post-hoc analysis; only study applicable to U.S. population

• Yu et al., 1991, China, indicated Se per se decreased liver cancer

• Blot et al., 1993, 1995, China, Se containing multi-nutrient decreased stomach cancer

FDA determined evidence to be limited and not conclusive.

What’s Needed?What’s Needed?

• Well controlled clinical trials

• Substance well defined

• Well defined and measured surrogate endpoints that demonstrate risk reduction

• If validated endpoints lacking, then trials need to be of long enough duration to measure incidence of disease

Food Labeling InformationFood Labeling Information

www.cfsan.fda.gov/label.html