1. 1 FDA Regulation of Product Claims January 25, 2011 Barbara A. Binzak, Ph.D., J.D., M.A. Attorney Buchanan Ingersoll & Rooney PC Washington, D.C. 202-452-7906barbara.binzak@bipc.com

2. 2 Outline Definition of probiotics Definition of probiotics FDA regulation of claims – key principles FDA regulation of claims – key principles FDA vs. Federal Trade Commission (FTC) FDA vs. Federal Trade Commission (FTC) Summary of claims regulation by product category Summary of claims regulation by product category –Drug (21 U.S.C. § 321(g)) –Dietary Supplement (21 U.S.C. § 321(ff)) –“Conventional” Food (21 U.S.C. § 321(f)) –Medical Food (21 U.S.C. § 360ee(b)(3)) –Device (21 U.S.C. § 321(h)) –Cosmetic (21 U.S.C. § 321(i)) –“Others” –Combination Products (21 C.F.R. § 3.2(e))

3. 3 What are Probiotics? “Live microorganisms, which, when administered in adequate amounts, confer a health benefit on the host.” - United Nations Food and Agricultural Organization (FAO)/World Health Organization (WHO) “Live microorganisms, which, when administered in adequate amounts, confer a health benefit on the host.” - United Nations Food and Agricultural Organization (FAO)/World Health Organization (WHO) Panel’s task is to determine how probiotics should be regulated Panel’s task is to determine how probiotics should be regulated –Is the current FDA regulatory scheme adequate? –Should Congress/FDA create a new regulatory paradigm? How do claims influence product regulation, and how does product regulation affect the product claims available? How do claims influence product regulation, and how does product regulation affect the product claims available? How - or should - product claims affect probiotic regulation? How - or should - product claims affect probiotic regulation?

4. 4 Key Principles (1) You are what you claim! You are what you claim! FDA looks at the available objective evidence to determine how a manufacturer intends its product to be regulated FDA looks at the available objective evidence to determine how a manufacturer intends its product to be regulated To determine intent, FDA will look at the product’s To determine intent, FDA will look at the product’s –Label (a ffixed to immediate container (21 U.S.C. § 321(k)); and –Labeling (l abels plus other written, printed, or graphic matter affixed to or accompanying the article (21 U.S.C. § 321(m)) ; and –Other promotional materials and activities (e.g., sales personnel; trade shows); and –Advertising

5. 5 Key Principles (2) Type of product (regulatory category) largely guides type/scope of claims and FDA’s oversight Type of product (regulatory category) largely guides type/scope of claims and FDA’s oversight –FDA often thinks “in the box” Products with FDA pre-approval requirements may have more defined requirements Products with FDA pre-approval requirements may have more defined requirements –E.g., Rx drug claims are approved by FDA and are product-specific –E.g., Dietary supplements are not pre-approved by FDA and claims are not product-specific May not introduce any food, drug, device, or cosmetic into interstate commerce that is adulterated or misbranded (21 U.S.C. § 331(a)) May not introduce any food, drug, device, or cosmetic into interstate commerce that is adulterated or misbranded (21 U.S.C. § 331(a)) In general, labels and labeling may not be false or misleading In general, labels and labeling may not be false or misleading

6. 6 FDA vs. FTC FDA FDA –Truth/falsity of advertising Rx drugs Rx drugs Restricted devices Restricted devices –Misbranding Foods Foods Drugs Drugs Devices Devices Cosmetics Cosmetics –Labeling Rx drugs Rx drugs OTC drugs OTC drugs FTC FTC –Truth/falsity of advertising OTC drugs Food Devices Cosmetics * This presentation covers FDA’s regulation of labeling, not advertising

7. 7 Drug Claims (1) What is a “drug”? (21 U.S.C. § 321(g)) What is a “drug”? (21 U.S.C. § 321(g)) –Articles recognized in USP, HPUS, or NF; and –Articles intended for use in diagnosis, cure, mitigation, treatment, or prevention of disease; and –Articles (other than food) intended to affect the structure or function of the body; and –Articles intended for use as components in any of the above

8. 8 Drug Claims (2) OTC drugs OTC drugs –Developed through public monograph process (i.e., notice and comment rulemaking; publication of notices in the Federal Register) –Claims for particular classes of drugs are set forth in FDA’s regulations However, some OTC drugs are approved with new drug applications (NDAs), and some begin as Rx drugs and later become OTC (“OTC switch”) However, some OTC drugs are approved with new drug applications (NDAs), and some begin as Rx drugs and later become OTC (“OTC switch”) –Claims for these products are established in NDA –E.g., OTC monograph for antacid drugs: “For the relief of heartburn, sour stomach, and/or acid indigestion” (and permitted variations)

9. 9 Drug Claims (3) Rx drugs Rx drugs –Claims must be consistent with FDA’s drug approval Scope of claims approval depends upon evidence supplied Scope of claims approval depends upon evidence supplied –Claims must be truthful and supported by “substantial evidence” Adequate and well-controlled investigations, including clinical investigations, that can form the basis on which experts can fairly and responsibly conclude that the drug has the effect it purports or is represented to have under the conditions set forth in the product labeling (21 U.S.C. § 355(d)) Adequate and well-controlled investigations, including clinical investigations, that can form the basis on which experts can fairly and responsibly conclude that the drug has the effect it purports or is represented to have under the conditions set forth in the product labeling (21 U.S.C. § 355(d)) FDA may determine, based on relevant science, that data from 1 adequate and well-controlled clinical investigation + confirmatory evidence are sufficient to establish substantial evidence (21 U.S.C. § 355(d)) FDA may determine, based on relevant science, that data from 1 adequate and well-controlled clinical investigation + confirmatory evidence are sufficient to establish substantial evidence (21 U.S.C. § 355(d))

10. 10 Dietary Supplement Claims (1) What is a “dietary supplement”? (21 U.S.C. § 321(ff)) What is a “dietary supplement”? (21 U.S.C. § 321(ff)) –Product intended to supplement the diet bearing or containing one or more Vitamin Vitamin Mineral Mineral Herb/botanical Herb/botanical Amino acid Amino acid Dietary substance to supplement the diet by increasing total dietary intake Dietary substance to supplement the diet by increasing total dietary intake Concentrate, metabolite, etc. of any of the above; and Concentrate, metabolite, etc. of any of the above; and –Intended for ingestion; and –Not represented as a conventional food or as sole item of meal/diet; and –Labeled as a dietary supplement

11. 11 Dietary Supplement Claims (2) Types of claims Types of claims –Health claims –Nutrient content claims –Structure/function (S/F) claims Manufacturers must ensure validity of product claims, but requirements for each type vary Manufacturers must ensure validity of product claims, but requirements for each type vary

12. 12 Dietary Supplement Claims (3) Health Claims - Describe relationship (explicit or implied) between food/food component/dietary supplement ingredient (“substance”) and reduced risk of a disease or health-related condition Health Claims - Describe relationship (explicit or implied) between food/food component/dietary supplement ingredient (“substance”) and reduced risk of a disease or health-related condition Types Types –Authorized – Requires “significant scientific agreement” Characterize relationship between substance and disease risk Characterize relationship between substance and disease risk Based upon totality of public scientific evidence Based upon totality of public scientific evidence Pre-reviewed; FDA issues regulations Pre-reviewed; FDA issues regulations E.g., Calcium, vitamin D, and osteoporosis: “Adequate calcium throughout life, as part of a well-balanced diet, may reduce the risk of osteoporosis” (21 C.F.R. § 101.72) E.g., Calcium, vitamin D, and osteoporosis: “Adequate calcium throughout life, as part of a well-balanced diet, may reduce the risk of osteoporosis” (21 C.F.R. § 101.72) E.g., Sodium and hypertension: “Diets low in sodium may reduce the risk of high blood pressure, a disease associated with many factors” (21 C.F.R. § 101.74) E.g., Sodium and hypertension: “Diets low in sodium may reduce the risk of high blood pressure, a disease associated with many factors” (21 C.F.R. § 101.74)

13. 13 Dietary Supplement Claims (4) Types of health claims (cont’d.) Types of health claims (cont’d.) –Qualified – Requires less evidence than “significant scientific agreement” Use emerging evidence of a relationship between substance and reduced risk of disease or health-related condition Use emerging evidence of a relationship between substance and reduced risk of disease or health-related condition FDA does not issue regulations; file petition and FDA issues letter of enforcement discretion FDA does not issue regulations; file petition and FDA issues letter of enforcement discretion Require disclaimer explaining level of scientific evidence support Require disclaimer explaining level of scientific evidence support E.g., cardiovascular disease risk - nuts and heart disease (“Scientific evidence suggests but does not prove that eating 1.5 ounces per day of most nuts [optional: such as name of specific nut] as part of a diet low in saturated fat and cholesterol may reduce the risk of heart disease”) E.g., cardiovascular disease risk - nuts and heart disease (“Scientific evidence suggests but does not prove that eating 1.5 ounces per day of most nuts [optional: such as name of specific nut] as part of a diet low in saturated fat and cholesterol may reduce the risk of heart disease”) E.g., diabetes risk - chromium picolinate and diabetes (“ E.g., diabetes risk - chromium picolinate and diabetes (“One small study suggests that chromium picolinate may reduce the risk of insulin resistance, and therefore possibly may reduce the risk of type 2 diabetes. FDA concludes, however, that the existence of such a relationship between chromium picolinate and either insulin resistance or type 2 diabetes is highly uncertain”)

14. 14 Dietary Supplement Claims (5) Nutrient Content Claims – Characterize nutrient levels Nutrient Content Claims – Characterize nutrient levels Most claim regulations apply only to nutrients/dietary substances that have an established daily value Most claim regulations apply only to nutrients/dietary substances that have an established daily value –FDA issues regulations Types Types –Describe level of a nutrient or dietary substance in the product (e.g., free; high; low) (21 C.F.R. Part 101, Subpart D) –Compare level of a nutrient in a food to that of another food (e.g., more; reduced; lite) (21 C.F.R. Part 101, Subpart D) –“Healthy” defined by regulation as implied nutrient content claim characterizing food with respect to total fat, saturated fat, cholesterol, and sodium (21 C.F.R. § 101.65(d)(2)) –Simple or comparative percentage claims for dietary supplements describe a % level of a dietary ingredient for which there is no established DV (e.g., “40% omega-3 fatty acids, 10 mg per capsule”) (21 C.F.R. § 101.13(q)(3)(ii))

15. 15 Dietary Supplement Claims (6) Structure/Function (S/F) Claims – Address role of a nutrient with respect to S/F of body Structure/Function (S/F) Claims – Address role of a nutrient with respect to S/F of body Historically appeared on conventional food, dietary supplement, and drug labels Historically appeared on conventional food, dietary supplement, and drug labels –DSHEA established special rules for dietary supplements Requires “disclaimer” language (i.e., FDA has not evaluated the claim) Requires “disclaimer” language (i.e., FDA has not evaluated the claim) Must have substantiation that claim is not truthful or misleading; notify FDA of claim no later than 30d after first marketing of product Must have substantiation that claim is not truthful or misleading; notify FDA of claim no later than 30d after first marketing of product Types Types –Describe role of nutrient/dietary ingredient that is intended to affect normal S/F (e.g., “calcium builds strong bones”) –Characterize means by which nutrient/dietary ingredient acts to maintain S/F (e.g., “fiber maintains bowel regularity”) –Describe general well-being from consumption of nutrient/dietary ingredient –Describe benefit related to nutrient deficiency disease as long as statement tells how widespread the disease is in the U.S. (e.g., vitamin C and scurvy)

16. 16 “Conventional” Food Claims (1) What is a “food”? (21 U.S.C. § 321(f)) What is a “food”? (21 U.S.C. § 321(f)) –Articles used for food or drink; and –Chewing gum; and –Articles used as components of “any such article” Use “conventional” food to distinguish between dietary supplements, medical foods, and other products that are classified under the umbrella term “food” Use “conventional” food to distinguish between dietary supplements, medical foods, and other products that are classified under the umbrella term “food”

17. 17 “Conventional” Food Claims (2) Similar to dietary supplement claims, but some differences Similar to dietary supplement claims, but some differences –Health claims Permits an additional type of health claim: Health claim based on authoritative statements by scientific body of U.S. government or Nat’l. Academy of Sciences Permits an additional type of health claim: Health claim based on authoritative statements by scientific body of U.S. government or Nat’l. Academy of Sciences E.g., "Diets rich in whole grain foods and other plant foods and low in total fat, saturated fat, and cholesterol may reduce the risk of heart disease and some cancers” E.g., "Diets rich in whole grain foods and other plant foods and low in total fat, saturated fat, and cholesterol may reduce the risk of heart disease and some cancers” –S/F claims Focus on effects derived from nutritive value Focus on effects derived from nutritive value –For dietary supplements, S/F claims may focus on both nutritive and non-nutritive effects No notification to FDA No notification to FDA No disclaimers required No disclaimers required

18. 18 Medical Food Claims (1) What is a “medical food”? (21 U.S.C. § 360ee(b)(3)) What is a “medical food”? (21 U.S.C. § 360ee(b)(3)) –Food which is formulated to be consumed or administered enterally (through GI tract, whether orally or by tube) under a physician’s supervision and which is intended for specific dietary management of a disease or condition for which distinctive nutritional requirements (based on recognized scientific principles) are established by medical evaluation

19. 19 Medical Food Claims (2) Medical foods are exempt from normal food labeling regulations (21 C.F.R. § 101.9(j)(8)); exemption applies only if product is Medical foods are exempt from normal food labeling regulations (21 C.F.R. § 101.9(j)(8)); exemption applies only if product is –Specially formulated and processed for partial or exclusive feeding of patient orally or by enteral tube; and –Intended for dietary management of a patient when cannot be achieved by modifying the normal diet (e.g., chronic medical needs; limited/impaired capacity to ingest, digest, etc.; other special medically-determined nutrient needs); and –Provides nutritional support to manage unique nutrient needs resulting from a specific disease/condition (per medical evaluation); and –Intended for use only under medical supervision; and –Intended only for patient receiving active/ongoing medical supervision

20. 20 Medical Food Claims (3) FDA proposed to evaluate its medical foods oversight FDA proposed to evaluate its medical foods oversight –No medical food regulations (61 Fed. Reg. 60661 (November 29, 1996)) FDA: “…point to the need for a strong standard of scientific evidence for the composition and effectiveness of medical foods.” FDA: “…point to the need for a strong standard of scientific evidence for the composition and effectiveness of medical foods.” FDA: “The agency’s preliminary view is that the scientific standard contained in the statutory medical food definition may require some of the same types of data for medical foods as are needed to support drug claims (e.g., data from clinical investigations).” FDA: “The agency’s preliminary view is that the scientific standard contained in the statutory medical food definition may require some of the same types of data for medical foods as are needed to support drug claims (e.g., data from clinical investigations).” Examples of purported medical food claims Examples of purported medical food claims –Restrict phenylalanine/PKU – “A phenylalanine-free food to aid in the nutritional management of hyperphenylalaninemia including PKU.” –Hypermetabolic states, such as severe burns, trauma, or infection – “A nutritionally complete formula that provides a concentrated source of calories for patients with restricted fluid allowance or increased energy needs…useful in the dietary management of volume-restricted patients, oncology patients, hypermetabolic conditions, trauma, sepsis, and post major surgery.”

21. 21 Device Claims (1) What is a “device”? (21 U.S.C. § 321(h)) What is a “device”? (21 U.S.C. § 321(h)) –An instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article (including any component, part, or accessory), which is: Recognized in the USP or NF; or Recognized in the USP or NF; or Intended for diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease; or Intended for diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease; or Intended to affect the structure or any function of the body; and Intended to affect the structure or any function of the body; and –Does not achieve its primary intended purposes through chemical action within or on the body and which is not dependent on being metabolized for the achievement of the primary intended purposes

22. 22 Device Claims (2) Two regulatory tracks Two regulatory tracks –Premarket Approval Application (PMA) (21 C.F.R. Part 814) Requires FDA pre-approval Requires FDA pre-approval Application includes indications for use plus a summary of supportive studies Application includes indications for use plus a summary of supportive studies Claims formulated during device development process Claims formulated during device development process –Premarket Notification (510(k)) (21 C.F.R. Part 807, Subpart E) Demonstrates that the proposed device is substantially equivalent (not identical) to a predicate device Demonstrates that the proposed device is substantially equivalent (not identical) to a predicate device –Substantial evidence based upon intended use and technological characteristics Must have support to demonstrate substantial equivalence Must have support to demonstrate substantial equivalence Claims often similar to those of the predicate device Claims often similar to those of the predicate device FDA must declare substantial equivalence before marketing FDA must declare substantial equivalence before marketing

23. 23 Cosmetic Claims (1) What is a “cosmetic”? (21 U.S.C. § 321(i)) What is a “cosmetic”? (21 U.S.C. § 321(i)) –Articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body or any part thereof for cleansing, beautifying, promoting attractiveness, or altering the appearance; and –Articles intended for use as a component of any of the above; and –Does not include “soap”

24. 24 Cosmetic Claims (2) FDA does not pre-approve labeling; may not label a cosmetic to implicate FDA approval FDA does not pre-approve labeling; may not label a cosmetic to implicate FDA approval Promoting a product with claims about disease treatment/ Promoting a product with claims about disease treatment/ prevention or about affecting S/F of body may cause the product to be a drug Product that is both an OTC drug and a cosmetic must comply with both OTC drug and cosmetic labeling requirements Product that is both an OTC drug and a cosmetic must comply with both OTC drug and cosmetic labeling requirements –E.g., antidandruff shampoos; toothpastes with fluoride; antiperspirant/deodorants; makeup with sun-protection claims Suspect claims (although significant lack of enforcement) (FDA Import Alert 66-38) Suspect claims (although significant lack of enforcement) (FDA Import Alert 66-38) –“anti-aging” –“counteract,” “retard,” or “control” aging –“rejuvenate,” “repair,” or “restructure” skin

25. 25 Others (1) Food for Special Dietary Use/Special Dietary Food (21 C.F.R. § 105.3(a)(1)) Food for Special Dietary Use/Special Dietary Food (21 C.F.R. § 105.3(a)(1)) –Particular uses of food for Supplying particular dietary needs existing due to physical, physiological, pathological, or other condition (e.g., diseases; convalescence; pregnancy; lactation, allergic hypersensitivity to food; underweight; overweight); and Supplying particular dietary needs existing due to physical, physiological, pathological, or other condition (e.g., diseases; convalescence; pregnancy; lactation, allergic hypersensitivity to food; underweight; overweight); and Supplying particular dietary needs existing by reason of age (e.g., infancy and childhood); and Supplying particular dietary needs existing by reason of age (e.g., infancy and childhood); and Supplementing or fortifying ordinary or usual diet with a vitamin, mineral, or other dietary property Supplementing or fortifying ordinary or usual diet with a vitamin, mineral, or other dietary property Biological Product (42 U.S.C. § 262(i)) Biological Product (42 U.S.C. § 262(i)) –A virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition –If have a biologics license application (BLA), do not need an NDA; however, most of Federal Food, Drug, and Cosmetic Act still applies to biologicals –Claims are product-specific

26. 26 Others (2) A variety of other terms are popularly used to refer to combination product categories A variety of other terms are popularly used to refer to combination product categories –Used in different manners –No legal meaning –Examples “Cosmeceutical” - “Cosmetic” + “pharmaceutical” “Cosmeceutical” - “Cosmetic” + “pharmaceutical” “Neutraceutical” - “Nutrition” + “pharmaceutical” “Neutraceutical” - “Nutrition” + “pharmaceutical” “Farmaceutical” - “Farm” + “pharmaceutical” “Farmaceutical” - “Farm” + “pharmaceutical” “Functional Food” - Food supplying a health/disease prevention benefit “Functional Food” - Food supplying a health/disease prevention benefit

27. 27 Combination Product Claims (1) What is a “combination product”? (21 C.F.R. § 3.2(e)) What is a “combination product”? (21 C.F.R. § 3.2(e)) –Product comprised of 2 or more regulated components that are physically, chemically, or otherwise combined or mixed and produced as single entity E.g., drug + device E.g., drug + device E.g., biologic + device E.g., biologic + device E.g., drug + biologic E.g., drug + biologic E.g., drug + device + biologic E.g., drug + device + biologic –Two or more separate products packaged together in a single package or as a unit comprised of a biologic, drug, and/or device FDA recognizes that there are other combinations possible, even though not recognized by regulation FDA recognizes that there are other combinations possible, even though not recognized by regulation –E.g., drug/device/biologic + dietary supplement/cosmetic/food

28. 28 Combination Product Claims (2) Office of Combination Products (OCP) Office of Combination Products (OCP) –Classifies single-entity products when category unclear –Determines jurisdiction/lead Center when combination product Jurisdiction can be shared Jurisdiction can be shared One Center will have primary oversight One Center will have primary oversight –Center jurisdiction assigned based upon product’s primary mode of action (PMOA) Sponsor can submit proposal for which Center should have oversight Sponsor can submit proposal for which Center should have oversight –Centers may collaborate with each other Combination product claims depend upon Combination product claims depend upon –Nature of individual components –Assignment of lead Center –Intercenter agreement on scope of claims

29. 29 Conclusions You are what you claim! You are what you claim! Do probiotics fit within one or several of these FDA regulatory schemes? Do probiotics fit within one or several of these FDA regulatory schemes? How is your view of probiotic regulation influenced by FDA’s oversight of product claims? How is your view of probiotic regulation influenced by FDA’s oversight of product claims?