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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

Update

• Overall• NDI• SAER• cGMP• Other

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

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

From FVM strategic plan

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)

NDI

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

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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

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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

A few examples of notable “objections”

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

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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

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.”

History of NDI draft guidance

• 111th Congress- S. 3002 & Full Implementation of DSHEA

• 111th Congress - Some elements folded into S. 510 became FSMA

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.”

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

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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

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• 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.”

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Next steps

• We continue to review comments• Timeline unknown for any decisions at

present

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• 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

Non-guide NDI matters

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

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;

SAERs

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

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

Year Mandatory Voluntary Both voluntary and

mandatory

Total cases per year

Deaths per year

2008 677 430 12 1119 12

2009 705 581 20 1306 24

2010 985 391 19 1395 23

2011 2019 430 24 2473 32

Total cases by report type 4386 1832 75 6293 91

GAO on AERs

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

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.".

• 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..

• 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).

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

cGMPs – 21 CFR Part 111

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)

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

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What investigators are finding during their inspections

• Failure to prepare a batch record– Unique identifier– Actual yield– Documentation at time of performance

What investigators are finding during their inspections

• Failure to establish specifications– Identity– Purity, strength and composition– Limits on contaminants

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

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

cGMP Enforcement Options

• WLs• Seizure• Injunction• Criminal Penalties

Other matters

• Tainted DS• OIG on FDA – Str/Fn Statements and

Registration under BT• Nanotech Guidance

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

Tainted Weight Loss Supplements JFK Int. Mail Facility

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Importation Through Mail Facility

Raw ingredient and finished product are often misdeclared and include false return addresses

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

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)

Guilty Plea

• AR fined $500,000• ND forfeited $100,000• Must pay for

independent monitoring and testing of all products for 5 years

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

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

Enforcement Challenges• Foreign manufacturers of finished product or ingredients• Sold on 1000s of websites, domestic and foreign• One product may be sold on 100s of websites AND e-

commerce sites (e.g. eBay, Amazon)• Domestic sites often operated from residences, fictitious

address, P.O. boxes • Dealers may order directly from foreign sources using

email, Skye, etc., or from e-commerce sites like Alibaba.com

• Suppliers solicit US dealers (email, “work at home schemes”)

• Often imported using international mail rather than legal declared imports

Tainted Products Links• Tainted Products Widget

http://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/MedicationHealthFraud/ucm242603.htm

• RSS feed: http://www.fda.gov/AboutFDA/ContactFDA/StayInformed/RSSFeeds/TDS/rss.xml

• Tainted Products listhttp://www.accessdata.fda.gov/scripts/sda/sdNavigation.cfm?sd=tainted_supplements_cder

• Reporting: TaintedProducts@fda.hhs.gov

In closing• over 400 recalls of spiked products since 2008 • OAI on GMPs (+ VAI) = more non-compliance

than compliance with cGMPs• only ~50 NDINs annually• Indication and Growing Evidence of

Underreporting of AERs• Increase in Claim WLs in 2011 (2012 tracking

upwards)• Evident of Systemic Issues

Questions?