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Dietary Supplement Overview/Update

Comments by

Daniel S. Fabricant, Ph.D.Director, Division of Dietary Supplements

ONLDS, CFSAN

daniel.fabricant@fda.hhs.gov

The pillars

• NDIs/Ingredient Safety

• cGMPs

• Claims

• Spiked products

• AERs

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

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

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

Supplement Industry Sales & Growth ‘94-’17e

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

Other Organizational Units

• ORA– Inspections– Investigations/enforcement actions– Imports

• OCC– Legal services

• OCI– Criminal investigations

From FVM strategic plan

http://www.fda.gov/Food/NewsEvents/ConstituentUpdates/ucm273365.htm

Is it a Dietary Supplement?

• Intended to supplement the diet?

• Contain dietary ingredients?

• Meet other criteria?

• Disease or structure/function claims?

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)

“Intended to supplement the diet”

• Supplement: “augment diet to promote health and reduce risk of disease”

• Diet: “usual food or drink of man”

“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

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

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)

“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

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)

“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)

“Intended for ingestion”

• Does not include– External/topical/patch products– Mouthwashes, rinses– Nasal/inhaled products– Sub-linguals– Certain lozenges and related products– Injection, suppository

“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

“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

“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)

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

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

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.

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

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)

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

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

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”

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

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

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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

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 isn’t final or QC-ed

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: 34137

*-accounting isn’t final or QC-ed

2012

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

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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

1996

1998

2000

2002

2004

2006

2008

2010

2012

CourtesyLetters

Structure Function Final Rule

Courtesy Letters Issued by FDA per Year to DS Firms for MakingDisease Claims in 30-Day Structure Function Notifications

Disease Claims Cited by Category1996 Infection, Inflammation, Prostate, Cancer

1997 Lower Cholesterol, Inflammation, Infection, Prostate, Immunodeficiency, Diabetes, Pain

1998 Infection, Mental Illness, Prostate, Cardiovascular, Immunodeficiency

1999 Infection, Allergy, Inflam., Addictions, Pain, Defects in Embryogenesis, Immunodef.

2000 Lower Cholesterol, Diabetes, Inflammation, Infection, BP, Pain, Blood Flow Through Arteries

2001 Lower Cholesterol, Diabetes, Inflammation, Pain, Allergy, Infection

2002 Pain, Inflammation, Infection, Lower Cholesterol, BP, Diabetes

2003 BP, Infection, Lower Cholesterol, Pain, Inflammation, Diabetes, Allergy

2004 Infection, Lower Cholesterol, Pain, Inflammation, Diabetes, BP

2005 Lower Cholesterol, Diabetes, Inflammation, Pain, Allergy, Infection

2006 Infection, Diabetes, Lower Cholesterol, BP, Pain, Inflammation

2007 Pain, Infection, Diabetes, Inflammation, BP, Lower Cholesterol, Prostate

2008 Inflammation, Infections, Lower Cholesterol, BP, diabetes

2009 Inflammation, Diabetes, Infections, Blood Flow Through Arteries

2010 Inflammation, Pain, Infections, Diabetes, Hangover

2011 Pain, Inflammation, Diabetes

2012Pain, Inflammation, Lower Cholesterol, BP, Allergy, Diabetes, Sleep, Cardiovascular,

Anemia

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• 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

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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

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

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?

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).

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)

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

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

FDA’s 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

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

Other thoughts/potential Q’s• 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?

• 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?

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.".

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.

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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)

• 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).