Dietary Supplement Overview/Update

1. Dietary Supplement Overview/Update Comments by Daniel S. Fabricant, Ph.D. Director, Division of Dietary Supplements ONLDS, CFSAN daniel.fabricant@fda.hhs.gov

2. The pillars • NDIs/Ingredient Safety • cGMPs • Claims • Spiked products • AERs

3. Statutory Authority Federal Food, Drug, and Cosmetic Act (21 U.S.C. § 301 et. seq.) Dietary Supplement Health and Education Act of 1994 (Pub. L. 103-417, 108 Stat. 4325) Dietary Supplement and Nonprescription Drug Consumer Protection Act (Pub. L. 109-462, 120 Stat. 3469) Farm Security and Rural Investment Act of 2002 (Pub. L. 107-171, 116 Stat. 135-527) Food Allergen Labeling and Consumer Protection Act of 2004 (Pub. L. 108-282, 118 Stat. 905) Public Health Security and Bioterrorism Preparedness and Response Act of 2002 (Pub. L. 107-188, 116 Stat. 594) FDA Food Safety Modernization Act (Pub. L. 111-353, 124 Stat. 3885

4. Dietary Supplements In 1 year - 3rd Decade of DSHEA Approx. 400 recalls of spiked products since 2008 ~33% OAI on GMPs (slightly higher VAI) only ~50 NDINs annually Indication and Evidence of underreporting of AERs Increase in Claim WLs in 2011 and 2012 Evident of Systemic issues

5. General General Regulatory Paradigm Very, very limited premarket review – No Premarket approval No formulation standards No product registration No approval of claims Manufacturer responsible for ensuring safety and compliance Where to find Information Statutes (15, 21 & 42 U.S.C) Code of Federal Regulations (Title 21) Guidances

6. Supplement Industry Sales & Growth ‘94-’17e

7. Organizational Responsibilities • CFSAN – program and policy issues • CDER - unapproved or misbranded drugs • ORA – field activities/enforcement • OCC – legal issues • OCI – criminal investigations • e.g., http://www.justice.gov/usao/mow/news2010/lor.ple.htm

8. Other Organizational Units • ORA • Inspections • Investigations/enforcement actions • Imports • OCC • Legal services • OCI • Criminal investigations

9. From FVM strategic plan http://www.fda.gov/Food/NewsEvents/ConstituentUpdates/ucm273365.htm

11. Is it a Dietary Supplement? • Intended to supplement the diet? • Contain dietary ingredients? • Meet other criteria? • Disease or structure/function claims?

12. What is a dietary supplement? “…a product (other than tobacco) intended to supplement the diet that bears or contains one or more...” dietary ingredients 21 U.S.C. §321(ff)(1)

13. “Intended to supplement the diet” • Supplement: “augment diet to promote health and reduce risk of disease” • Diet: “usual food or drink of man”

14. “Intended to supplement the diet” • Illicit street drug policy: “get high/euphoria” • (62 FR 30678 at 30699; guidance; US vs Und. Qty. of Articles of Drug, 145 F. Supp. 2d 692 (D. MD. 2001) • Mask or counter urine drug tests

15. Is it a Dietary Ingredient? • Vitamin, mineral, amino acid • Herb or other botanical • Dietary substance for use by man to supplement the diet by increasing the total dietary intake • “Dietary” – of or pertaining to the diet • “Diet” – usual food or drink of man • “substance” – that which has mass, occupies space, and can be perceived by the senses

16. Is it a Dietary Ingredient? • Concentrate, metabolite, constituent, extract or combination of any ingredient above • Synthetic substances? • Probably yes for “named” ingredients • No for botanical-derived substances and some “dietary substances”? (June 21, 2001 ltr. to L. Nagel, DEA; Homotaurine Petition)

17. “Dietary substance for use by man” • Does not mean “any” substance • Congress qualified “substance” • While it may be a broad universe of substances, it is still a limited universe

18. What is a dietary supplement? • Other Requirements • Intended for ingestion • Pill, capsule, liquid, powder, “other” forms • Not represented for use as a conventional food • Not a sole item of a meal or diet • Labeled a “dietary supplement” 21 U.S.C. §321 (ff)(2)

19. “Intended for ingestion” • Ordinary and plain meaning of “ingestion” • Take into stomach and gastrointestinal tract enterally US v. Ten Cartons, Ener-B Nasal Gel, 888 F. Supp. 381, 393-94 (E.D.N.Y.), aff’d, 72 F.3d 285 (2d Cir. 1995)

20. “Intended for ingestion” • Does not include • External/topical/patch products • Mouthwashes, rinses • Nasal/inhaled products • Sub-linguals • Certain lozenges and related products • Injection, suppository

21. “Represented for use as a conventional food” • Not the same as prior definition of “simulate conventional food” (i.e., conventional food form) • Generally, physical attributes of a food will not be primary determinant

22. “Represented for use as a conventional food” • Think “how is it used” or “what is it a substitute for” • called a snack or uses another common or usual food name • uses a standardized food name • uses label representations/pictures that suggest conventional food uses • Packaging and serving sizes

23. “Represented for use as a conventional food” • “Supplement soups” (Jun. 21, 1999 ltr., Hain Food Group) • Cereals (Jun. 5, 2001 WL, US Mills, Inc.) • Chewing gum • Beverages/drinks (74 FR 63759; Dec. 4, 2009 Draft Guidance)

24. Disease Definition • 21 CFR 101.93(g)(1) “[D]amage to an organ, part, structure, of system of the body such that it does not function properly…or a state of health leading to such dysfunctioning…” http://www.fda.gov/Food/DietarySupplements/GuidanceComplianceRegulatoryInformation/ucm107336.htm; January 6, 2000 Federal Register; 65 FR 999

25. Disease Claims • Explicit Claims • Prevent immunodeficiency syndrome • Prevent cold and flu / infection • Implicit Claims • Kill pathogenic microorganisms • Return CD4 cell counts to normal levels • Enhance antiviral defenses • Other Implicit Claims? • Boost immune defenses

26. Disease Claims • Intended use is based on manner in which the product is advertised or marketed (product labels and labeling, catalogs, brochures, audio and videotapes, Internet sites, or other circumstances surrounding the distribution of the product (including oral representations, testimonials, and other promotional activities). See 21 C.F.R. § 201.128.

27. Health Claims • Describe a relationship between substance and disease • Disease risk reduction only • Require prior authorization by FDA • General information at http://www.fda.gov/Food/LabelingNutrition/LabelClaims/default.htm

28. Structure/Function Claims • Nutrient deficiency disease • Affect a structure or function in humans • Mechanism by which…acts to maintain such structure or function • Describes general well-being from consumption 21 U.S.C. 343(r)(6)

29. Structure/Function Claims • May not claim to diagnose, treat, cure, or prevent any disease • Require mandatory disclaimer and post-marketing notification (21 CFR 101.93(a)-(e)) • Must have substantiation that statement is truthful and not misleading

30. Substantiation of Section 403(r)(6) Dietary Supplement Claims • Jan. 5, 2009 Federal Register; 74 FR 304 • http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/DietarySupplements/ucm073200.htm • Describe the nature of the claim and the amount, type, and quality of evidence

31. What is the substantiation standard? • “Competent and reliable scientific evidence” • “tests, analyses, research, studies, or other evidence based on the expertise of professionals in the relevant area, that has been conducted and evaluated in an objective manner by persons qualified to do so, using procedures generally accepted in the profession to yield accurate and reliable results”

32. 4 principal issues guide whether a claim is substantiated • Meaning of the claim being made • Relationship of the evidence to the claim • Quality of the evidence • Totality of the evidence

33. Pitfalls • Over-reliance on anecdotal/historical • Fail to consider negative evidence • Mistake number of publications as direct indicator of totality of evidence • Over-reliance on disease treatment studies • Not considering implied message/claims

35. cGMPs • FDA is finding that the basic tenets of cGMPs, and manufacturing in general, are not being adhered to, or in many instances are completely absent • This is concerning as there isn’t much help that the agency can offer to assist with compliance in these instances • Solutions

36. 21 CFR 111 Inspections* FY 2008 7 FY 2009 34 FY 2010 84 FY 2011 175 FY 2012341* FY 2013(10/23/2012) 10 *-accounting isn’t final or QC-ed

37. 21 CFR 111 Inspections* • FY 2012 Inspection Classification by field: • No Action Indicated: 92 27% • Voluntary Action Indicated: 119 35% • Official Action Indicated: 116 34% • No decision 14 4% • Total: 341 37 *-accounting isn’t final or QC-ed

38. 2012 • Non-cGMP or “mixed” cases reviewed/processed by DDSP • Detentions: 94 • Warning Letters (misbranding and DZ claims): 88 • Untitled Letters: 8

39. Claims More activity in the claims area recently Warning letters increased in 2012 – STD claims, concussion claims Greatest concern is claims that have an immediate impact on public health (e.g., claims that may lead to a delay in treatment) Close collaboration with FTC -- labeling vs. advertising

40. Courtesy Letters Issued by FDA per Year to DS Firms for Making Disease Claims in 30-Day Structure Function Notifications CourtesyLetters 1996 1998 2000 2002 2004 2006 2008 2010 2012 Structure Function Final Rule

41. Disease Claims Cited by Category

42. Tainted Products • FDA would like to see the industry take the matter very seriously and really urge companies to get the word out on tainted products • FDA continues to pursue cases in this area, if anyone in the industry is aware of people who are involved in producing tainted products they can report those to FDA directly through CFSAN or CDER program offices or we have anonymous tip-lines (i.e. OCI)

43. Tainted Products - Red Flags Most activity has been in the ED, weight loss, bodybuilding areas Newer areas – pain/inflammation, diabetes Mass solicitations (spam email, etc) Directions for use, such as Take 15 min to1 hr before sexual activity (ED) Take 1 in morning before breakfast (weight loss) “Works like” or “better than” Rx drug Labels in foreign language or “broken” English Label contraindications or warnings: pregnancy, cardiovascular disease, seizures

44. Dietary supplement adverse event reports, FDA-Center for Food Safety and Applied Nutrition Adverse Event Reporting System (CAERS), 2008 – 2011.Counts were obtained using FDA Received Date and year of first report for a case if there were multiple reports for a case (e.g., both a voluntary report and a mandatory report; follow-up reports); CAERS was searched on March 2012 for these counts; Submission will not be construed by FDA as an admission that the dietary supplement caused the Adverse Event

45. GAO on AERs

46. Serious Adverse Event Reporting SAER Challenges: (a) insufficient or inaccurate information in many case reports; (b) underreporting of adverse events; (c) data on background rates of adverse events as compared to those that are associated with dietary supplements; (d) data on extent of exposure to particular dietary supplements within the population. In light of challenges, how will the Agency use SAERs to determine acute, chronic and “mixed/combination” risk to supports the basis for causality, when and where appropriate?

47. Serious Adverse Event Reporting Lessons Learned Ingredients and products for which there is pharmacological or clinical evidence to support the plausibility of certain serious adverse events could be enough to make a determination. Concerning insufficient information, follow-up becomes critical in "fleshing out" clinical evidence Also, with respect to challenge d) data on exposure may be less important if there are "plausible" serious adverse events that satisfy the evaluation criteria (challenge/rechallenge, etc).

48. Safety DSHEA added new adulteration provision in this regard Significant or unreasonable risk of injury of illness Conditions of use Ordinary conditions of use Didn’t exempt from existing requirements 21 U.S.C. 342(f)

49. FDA’s Standard Unreasonable risk Met when a product’s risks outweigh its benefits in light of claims and directions for use (or under ordinary conditions) See 69 FR 6787; Feb. 11, 2004

50. FDA’s Standard Relative weighing of known and reasonably likely risk against known and reasonably likely benefits Doesn’t require showing of causality Seriousness of risks and quality and persuasiveness of the totality of evidence to support the presence of those risks