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
– 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/p
ages/printerfriendly.csp?id=52397201
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 paperhttp://toxsci.oxfordjournals.org/content/123/2/333.f
10
ull
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
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
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.
nd
2
• 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
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/Transparen
cy/Basics/ucm194909.htm
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
Next steps
• We continue to review comments
• Timeline unknown for any decisions at
present
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.gov
240-402-1756
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 NonRx & 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/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).
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
36
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/Pres
sAnnouncements/ucm306348.htm
• 052612-Recall - V maxx (sulfoaildenafil) http://www.fda.gov/Safety/Recalls/ucm305795.ht
m
• 051812 – Recall – Firminite et al., (Tadalafil) http://www.fda.gov/Safety/Recalls/ucm304719.ht
m
• 041912 – Recall - Xrock
Tainted Weight Loss Supplements
JFK Int. Mail Facility
Importation Through Mail Facility
Raw ingredient and finished product are often misdeclared and include
false return addresses
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
Guilty Plea
01/17/2012
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 ecommerce 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/BuyingUsing
MedicineSafely/MedicationHealthFraud/ucm242603.htm
• RSS feed:
http://www.fda.gov/AboutFDA/ContactFDA/StayInformed/RSSFeeds/
TDS/rss.xml
• Tainted Products list
http://www.accessdata.fda.gov/scripts/sda/sdNavigation.cfm?sd=taint
ed_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?