Nutrition Related Regulatory Issues Kathleen Ellwood, Ph.D. Director, Division of Nutrition Programs and Labeling Office of Nutritional Products, Labeling, and Dietary Supplements

Topics To Be Covered Fortification Policy Biotechnology Labeling Guidance Health Claims

Fortification 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. 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. 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 Labeling Guidance Voluntary Labeling Indicating Whether Foods Have or Have Not Been Developed Using Bioengineering

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FDA Actions Held three public meetings in 1999 Conducted focus group studies Developed draft guidance in January, 2001

Biotechnology Draft Guidance Does not require special labeling of all bioengineered foods based on production method Restates agency’s policy regarding when special labeling is required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:

What It Takes To Get A Health Claim

Evidence-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  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 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 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 Validated Modifiable Risk Factors Disease/ Health Related Condition Disease Symptoms and Signs Drugs 21 USC 321 (g)(1)(B) Health Claim 21 USC 343(r)(5)(D) Substance

Diseases 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 Studies Studies involving healthy humans Studies that measure validated, modifiable risk factors Studies that measure reduced risk of disease or health related condition

Classify Studies Intervention studies – “ Gold standard” -- Measured modifiable risk factor, i.e. LDL- cholesterol soy protein and CHD walnuts and CHD -- Measured incidence of onset of disease omega-3 fatty acid and CHD fiber-containing grain products, fruit and vegetables and cancer

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 Quality Study design Data collection Inclusion and exclusion of study subjects Statistical methods/analysis + (good)  (moderate)  (poor)

Rate 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” 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” Qualified Health Claims Moderate/good level of comfort (B) Low level of comfort (C) Extremely low level of comfort (D)

Qualifying 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 Cancer

Selenium and Cancer Intervention 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 Cancer Intervention Studies – con’t. Multi-nutrient supplement provided - Not able to evaluate the effect of Selenium per se Blot et al., 1993, China Li et al., China Prasad et al., India Bonelli et al., Italy

Selenium and Cancer Observational Studies 36 Studies 16 prospective cohort studies, 3 retrospective case-control studies, 17 ecological and cross-sectional ½ supported an association for total cancers ½ 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 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? 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 Information