1. 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 - 3 rd 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.), affd, 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/GuidanceComplianceRegulatoryI nformation/ucm107336.htm; January 6, 2000 Federal Register; 65 FR 999ttp://www.fda.gov/Food/DietarySupplements/GuidanceComplianceRegulatoryI nformation/ucm107336.htm

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/LabelingNutrit ion/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/GuidanceComplianc eRegulatoryInformation/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. 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 isnt 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 2012 341* FY 2013 (10/23/2012) 10 *-accounting isnt 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 isnt 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. 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. 199619982000200220042006200820102012 Courtesy Letters Structure Function Final Rule Courtesy Letters Issued by FDA per Year to DS Firms for Making Disease Claims in 30-Day Structure Function Notifications

41. Disease Claims Cited by Category 1996Infection, Inflammation, Prostate, Cancer 1997Lower Cholesterol, Inflammation, Infection, Prostate, Immunodeficiency, Diabetes, Pain 1998Infection, Mental Illness, Prostate, Cardiovascular, Immunodeficiency 1999Infection, Allergy, Inflam., Addictions, Pain, Defects in Embryogenesis, Immunodef. 2000Lower Cholesterol, Diabetes, Inflammation, Infection, BP, Pain, Blood Flow Through Arteries 2001Lower Cholesterol, Diabetes, Inflammation, Pain, Allergy, Infection 2002Pain, Inflammation, Infection, Lower Cholesterol, BP, Diabetes 2003BP, Infection, Lower Cholesterol, Pain, Inflammation, Diabetes, Allergy 2004Infection, Lower Cholesterol, Pain, Inflammation, Diabetes, BP 2005Lower Cholesterol, Diabetes, Inflammation, Pain, Allergy, Infection 2006Infection, Diabetes, Lower Cholesterol, BP, Pain, Inflammation 2007Pain, Infection, Diabetes, Inflammation, BP, Lower Cholesterol, Prostate 2008Inflammation, Infections, Lower Cholesterol, BP, diabetes 2009Inflammation, Diabetes, Infections, Blood Flow Through Arteries 2010Inflammation, Pain, Infections, Diabetes, Hangover 2011Pain, Inflammation, Diabetes 2012Pain, Inflammation, Lower Cholesterol, BP, Allergy, Diabetes, Sleep, Cardiovascular, Anemia

42. 42 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) Tainted Products

43. 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 YearMandatoryVoluntaryBoth voluntary and mandatory Total cases per year Deaths per year 200867743012111912 200970558120130624 201098539119139523 2011201943024247332 Total cases by report type4386183275629391

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 Didnt exempt from existing requirements 21 U.S.C. 342(f)

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

50. FDAs Standard Relative weighing of known and reasonably likely risk against known and reasonably likely benefits Doesnt require showing of causality Seriousness of risks and quality and persuasiveness of the totality of evidence to support the presence of those risks

51. FDAs Standard Weight against importance of benefits and quality and persuasiveness of the totality of the evidence to support the existence of those benefits More weight to benefits that –Improve health outcomes –Not temporary –Not rely on subjective measures

52. Post-Market Surveillance - AERs and Product Complaints Reasonable Corporate Systems are likely Integrated PC are receiving, documenting and tabulating; AERs are the same + reporting requirement If trending and benchmarking are absent and/or deficient in cGMP regarding product complaints, what might this mean for other requirements? Assessment of a firms capabilities

53. Other thoughts/potential Qs Do you know the expected or normalized to sales incidence rate for all allegations of injury broken down by age and outcome? Do you have a way to track that number for trending to determine an accepted range and if there are unexplained variations to that range in any given time period? Based on the toxicology and design of the product, do you know what kinds of events you should expect to see, and then do you have a benchmark for how often they occur or are expected to occur?

54. For the events that occur, do you know which ones are predictable based on previous general use patterns consistent with known toxicology of the product, and do you know the incidence rate for just those events? Once you know these numbers, do you have a way to determine which reports of injury meet a high level of integrity for strengths of association between product use and reported effect, and which incidents meet lower levels of integrity for strengths of association for a relationship?

55. Whats wrong with this picture? Medwatch 800 number (c) MISBRANDING.Section 403 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 343) is amended by adding at the end the following: "(y) If it is a dietary supplement that is marketed in the United States, unless the label of such dietary supplement includes a domestic address or domestic phone number through which the responsible person (as described in section 761) may receive a report of a serious adverse event with such dietary supplement.".

57. Quincy Bioscience WL http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2012/ucm324557.htm Because your products are labeled as dietary supplements, FDA initially evaluated them under the laws and regulations governing dietary supplements, including the adverse event reporting and recordkeeping requirements for dietary supplements in section 761 of the Act, 21 U.S.C. § 379aa-1, and the current good manufacturing practice (CGMP) regulations for dietary supplements in 21 CFR Part 111. As noted on the list of inspectional observations issued to your headquarters and warehouse facility in Madison, Wisconsin, on December 22, 2011, our inspection of that facility revealed that you failed to report serious adverse events associated with your Prevagen products to FDA, as required by section 761(b)(1) of the Act. Specifically, you failed to report to FDA adverse events like seizures, strokes, and worsening symptoms of multiple sclerosis that had been reported to your firm as being associated with use of Prevagen products. Some of these adverse events resulted in hospitalization. In total, our inspection found records of more than 1000 adverse events and product complaints that had been reported to your firm between May 2008 and December 1, 2011. Some of these involved heart arrhythmias, chest pain, vertigo, tremors, and syncope (fainting), in addition to the seizures, strokes, and worsening of multiple sclerosis already mentioned. As of the beginning of the inspection, only two of these adverse events had been reported to FDA or investigated by your firm.

58. 58 Energy Drinks Many new products are being marketed Issue: Whether a product is a DS or a beverage (i.e., a conventional food) Developing guidance to address the issue (final guidance on distinguishing liquid dietary supplements from beverages)

59. FDA has taken action for firms that have failed to notify FDA of serious adverse event reports (AERs). The most significant example to date was the filing of a complaint for permanent injunction against the firm ATF/Made (http://www.fda.gov/NewsEvents/Newsroom/PressAnnou ncements/ucm281017.htm). The complaint, filed Nov. 23, 2011, in the U.S. District Court for the Western District of Pennsylvania, charged that in addition to adulterating and misbranding their final products, the manufacturer and its owner failed to report serious adverse events associated with their products, including one case where an individual who consumed one of the products reported experiencing a spike in blood pressure, hospitalization and a subsequent mild heart attack..

60. Other examples of recent FDA action on adverse events: –Nordimex Warning Letter - 403(y) citation "failure to furnish an address or phone number for adverse event reporting" (http://www.fda.gov/ICECI/EnforcementActions/Warni ngLetters/2011/ucm275369.htm); –BioSan warning letter - 403(y) citation "the label fails to bear a domestic address or domestic phone number through which the responsible person may receive a report of a serious adverse event associated with such dietary supplement." (http://www.fda.gov/ICECI/EnforcementActions/Warni ngLetters/ucm262443.htm).