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FDA Dietary Supplement Update

FDA Dietary Supplement Update. Daniel Fabricant, Ph.D. Director, Division of Dietary Supplement Programs, ONLDS, CFSAN daniel.fabricant@fda.hhs.gov Natural Marketplace June 15, 2012. 1. Update . Overall NDI SAER cGMP Other. General. General Regulatory Paradigm

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FDA Dietary Supplement Update

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  1. FDA Dietary Supplement Update Daniel Fabricant, Ph.D. Director, Division of Dietary Supplement Programs, ONLDS, CFSAN daniel.fabricant@fda.hhs.gov Natural Marketplace June 15, 2012 1

  2. Update • Overall • NDI • SAER • cGMP • Other

  3. General General Regulatory Paradigm Limited premarket review – No Premarket approval No formulation standards No product registration No approval of s/f 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

  4. 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

  5. From FVM strategic plan

  6. Dietary Supplements • over 400 recalls of spiked products since 2008 • OAI on GMPs (+ VAI) = more non-compliance (varying degrees) than compliance with cGMPs • only ~50 NDINs annually • Indication and Growing Evidence of underreporting of AERs • Increase in Claim WLs in 2011 (2012 tracking)

  7. NDI

  8. Salt Lake Tribune “I think most people in the industry would say we have been under-filing in the last few years,” http://www.sltrib.com/csp/cms/sites/sltrib/pages/printerfriendly.csp?id=52397201

  9. NDI FDA Response Options • Acknowledgement • Objections can be categorized as follows: • The notification contained unresolved safety concerns (identity or toxicology issues); • The notification was incomplete; or • The notification was objected to for other reasons, e.g., the substance that was the subject of the notification was an approved drug or did not meet the definition of a dietary ingredient. • ToxSci paper- http://toxsci.oxfordjournals.org/content/123/2/333.full 10

  10. A few examples of notable “objections” • Unresolved Safety: • Germanium;Pyrrolizidine-containing seed oil (Echium plantagineum);Phytolacca americana lectins;Oleander extract (Nerium oleander) ;Gammabutyrolactone (GBL); E.coli; “Milkweed seed oil” • Non-Dietary Ingredients: • Cotinine; trans-resveratrol; Hyaluronic acid 11

  11. 2004 FR notice Federal Register / Vol. 69, No. 202 / Wednesday, October 20, 2004 Public Meeting Held on Nov. 15, 2004 Cited McGuffin/Young FDLI paper 12

  12. Background of draft guidance Sharfstein speech to 2009 CRN Annual meeting: “One such tool is the agency’s ability to review new dietary ingredients, or NDIs. An NDI is a dietary ingredient that was not marketed in the United States in a dietary supplement before October 15, 1994.Although DSHEA excludes from premarket notification “grandfathered” dietary ingredients that were marketed before DSHEA became law, dietary supplements that contain new dietary ingredients must submit a 75-day pre-market notification to FDA. This provides FDA a chance to review the safety of the supplement that contains the new dietary ingredient before consumers can use the product. Dietary supplements containing new dietary ingredients for which this notification is not provided are illegally marketed. So far, we have been hampered by the fact that no verified list of grandfathered ingredients exists. But here’s what we can do. We can set out guidance explaining how to demonstrate that a product is in fact grandfathered in. Then, when we see concerning products we do not believe were marketed prior to October 15, 1994 on the market, we can ask companies to provide evidence of prior marketing … or to voluntarily pull the product until an NDI premarket notification is filed. For this approach to work as well as possible, we must also provide clear standards and prompt review for new ingredients. This will allow us to support legitimate products … while acting to remove risky ingredients quickly from the market.” http://www.fda.gov/NewsEvents/Speeches/ucm187640.htm 13

  13. Background of draft guidance Senate Judiciary Senate Aging hearing (5/2010): http://aging.senate.gov/events/hr221sm.pdf -“What is needed, though, to increase success in filing NDI notifications, is a formal guidance from FDA that explains clearly the agency’s views on what constitutes a new dietary ingredient versus a grandfathered one and provides instruction on how firms can establish the reasonable expectation of safety from the evidence they provide. Industry has been asking for this guidance for years and FDA has been promising it, but to date, it has not been issued.”

  14. History of NDI draft guidance 111th Congress- S. 3002 & Full Implementation of DSHEA 111th Congress - Some elements folded into S. 510 became FSMA

  15. NDI Draft Guidance Background The FDA Food Safety and Modernization Act (FSMA) required FDA to publish NDI guidance not later than 180 days after the date of enactment. “Guidance represents the FDA's current thinking on this topic. It does NOT create or confer any rights for or on any person and does not operate to bind FDA or the public.”

  16. Comment Period closed Dec. 2nd From FDMS over 7,000 comments as of 12/8/2011 Some paper docs still being uploaded Thanks to all of those who commented 17

  17. Guidance v. Statute v. Regs What is the difference between the Federal Food, Drug, and Cosmetic Act (FD&C Act), FDA regulations, and FDA guidance? http://www.fda.gov/AboutFDA/Transparency/Basics/ucm194909.htm 18

  18. Good Guidance Practice (21 CFR 10.115): http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=10.115 • “Guidance documents do not establish legally enforceable rights or responsibilities. They do not legally bind the public or FDA.” • “One may choose to use an approach other than the one set forth in a guidance document. However, your alternative approach must comply with the relevant statutes and regulations. FDA is willing to discuss an alternative approach with you to ensure that it complies with the relevant statutes and regulations.” 19

  19. Next steps • We continue to review comments • Timeline unknown for any decisions at present 20

  20. To look at previous NDI notifications and FDA responses at regulations.gov docket FDA-1995-S-0039 Questions about a notification: NDI Consumer Safety Officer: CFSANddspNDI@fda.hhs.gov240-402-1756

  21. Non-guide NDI matters

  22. 1,3 –Dimethylamylamine (DMAA) • Open case • 15-days to respond, we have received responsed from all firms • Failed to file NDI per the statute was the cite in the WLs • New article in Arch. Int. Med. – DMAA as a DS ingredient – Pieter Cohen • High level of consumer/commercial press interest

  23. 402(f)(1)(B) A food shall be deemed to be adulterated— (f) Dietary supplement or ingredient: safety. • (1) If it is a dietary supplement or contains a dietary ingredient that— • (B) is a new dietary ingredient for which there is inadequate information to provide reasonable assurance that such ingredient does not present a significant or unreasonable risk of illness or injury;

  24. SAERs

  25. Authority & Responsibility in Non-Rx & DS Consumer Protection Act • 15-day mandatory submission requirement – submission by rule of construction does not establish causality • 1 year mandatory follow-up with any new & relevant information • Access to records • Record maintenance • Domestic address or phone required on the label

  26. 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

  27. GAO on AERs

  28. 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 firm’s capabilities

  29. What’s 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.".

  30. 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/PressAnnouncements/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..

  31. 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/WarningLetters/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/WarningLetters/ucm262443.htm).

  32. SAERs – take home • Submitting an AE does not establish a causal relationship to indicate the AE is unsafe; not submitting or failing to submit an AE does not indicate the product is safe, though it is a violation of the Act • Clear indications of underreporting are increasing – resource intensive to ensure compliance • Reasonable systems take a “holistic” approach to compliance/corporate responsibility

  33. cGMPs – 21 CFR Part 111

  34. cGMPs -21 CFR Part 111 • For FY’11 – 175 inspections • First Injunction citing 21 CFR Part 111 • First Seizure citing 21 CFR Part 111 • For FY’12 (PAC Code 21008A - 5/1/12): 38(NAI); 48 (VAI); 51 (OAI) • Subpart (E)

  35. What investigators are finding during their inspections. Failure to prepare a master manufacturing record. Specifications for each step in the manufacturing process Unique formulation for each batch Identity and weight Theoretical yield 36

  36. What investigators are finding during their inspections Failure to prepare a batch record Unique identifier Actual yield Documentation at time of performance

  37. What investigators are finding during their inspections Failure to establish specifications Identity Purity, strength and composition Limits on contaminants

  38. What investigators are finding during their inspections Failure to determine if specifications are met Tests to meet specifications Qualifying the supplier Documentation of how supplier was qualified

  39. What investigators are finding during their inspections Failure of adequate quality control Lack of review Lack of material review and disposition decision Lack of quality control procedures

  40. cGMP Enforcement Options • WLs • Seizure • Injunction • Criminal Penalties

  41. Other matters • Tainted DS • OIG on FDA – Str/Fn Statements and Registration under BT • Nanotech Guidance

  42. Tainted products • 060112-Reumofan Plus (methocarbamol & diclofenac sodium) - http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm306348.htm • 052612-Recall - V maxx (sulfoaildenafil) - http://www.fda.gov/Safety/Recalls/ucm305795.htm • 051812 – Recall – Firminite et al., (Tadalafil) - http://www.fda.gov/Safety/Recalls/ucm304719.htm • 041912 – Recall - Xrock

  43. Tainted Weight Loss Supplements JFK Int. Mail Facility

  44. Importation Through Mail Facility Raw ingredient and finished product are often misdeclared and include false return addresses 45

  45. Red Flags ED, weight loss, bodybuilding 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

  46. Guilty Plea01/17/2012 Anabolic Resources (AR) & Nutrition Distribution (ND) dba Anabolic Xtreme Distributed “supplements” containing: Superdrol (methasterone, a synthetic steroid) Hyperdrol (6-bromodione and androstenedione) Slim Xtreme (designer stimulant)

  47. Guilty Plea AR fined $500,000 ND forfeited $100,000 Must pay for independent monitoring and testing of all products for 5 years

  48. Indicted Novocare, SLC, UT Ex-official indicted for selling “100% natural and safe” ED products tainted with sildenafil analogs: “Stiff Nights”, “Natural Wow”, “Size Matters”, “OMG” “Not a drug” and “Better than Viagra” 1 count conspiracy, 12 counts wire and 9 counts mail fraud, 4 counts money laundering

  49. Criminal Sentencing June 3, 2011: Chinese national sentenced to over 7 yrs in federal prison for trafficking counterfeit “Alli” and tainted supplements. Texas ER doc suffered mild stroke Pay ½ million in restitution

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