Transcript Slide 1

Dietary Supplement
Overview/Update
Comments by
Daniel S. Fabricant, Ph.D.
Director, Division of Dietary Supplements
ONLDS, CFSAN
[email protected]
1
The pillars
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•
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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
$45,000
12%
$40,000
10%
$35,000
$30,000
8%
$25,000
6%
$20,000
$15,000
4%
$10,000
2%
$5,000
$0
0%
Non-Retail Growth
2017
2016
2015
2014
2013
2012
2011
Retail Growth
2010
2009
2008
2007
2006
2005
Growth
2004
2003
2002
2001
2000
1999
1998
1997
Sales $M
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/GuidanceComplianceRegulatoryI
nformation/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/LabelingNutrit
ion/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/GuidanceComplianc
eRegulatoryInformation/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
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
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21 CFR 111 Inspections*
•
•
•
•
•
•
FY 2008
FY 2009
FY 2010
FY 2011
FY 2012
FY 2013
(10/23/2012)
*-accounting isn’t final or QC-ed
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34
84
175
341*
10
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
– Total:
*-accounting isn’t final or QC-ed
14
341
4%
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2012
• Non-cGMP or “mixed” cases
reviewed/processed by DDSP
– Detentions: 94
– Warning Letters (misbranding and DZ claims): 88
– Untitled Letters: 8
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
39
Courtesy Letters Issued by FDA per Year to DS Firms for Making
Disease Claims in 30-Day Structure Function Notifications
140
120
100
Courtesy
Letters
80
60
40
20
0
Structure Function Final Rule
Disease Claims Cited by Category
1996
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
2012
Pain, Inflammation, Lower Cholesterol, BP, Allergy, Diabetes, Sleep, Cardiovascular, Anemia
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)
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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
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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.
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)
58
• 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..
• 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).