Transcript Slide 1

Safety of Dietary Supplements
Comments by Daniel Fabricant, Ph.D.
Director, Division of Dietary Supplement Programs,
ONLDS, CFSAN
[email protected]
February 8, 2013
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Safety
• DSHEA added new adulteration
provision
• 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
Hydroxycut
• Capsules, drinks/drink powders,
liquid shots
• From 5-20 ingredients/product
• Varying degrees of ingredient
overlap
• AERs per product from 0 to 31
• Formulations changed over time
Ingredients
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Garcinia cambogia ext. (HCA)
Green tea ext. (EGCG/catechins/caffeine)
Caffeine anhydrous
Gymnema sylvestre ext.
White tea ext.
Oolong tea ext.
Chromium
Soy lecithin
Quercetin dihydrate
Raspberry ketone
Rhodiola roseea ext.
Ginger ext.
Basic Facts
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Liver injury AEs provided the signal
Sept. 2008: Physicians contact FDA
CAERS search ID’d 18 cases
8 cases were 2002-04 for ephedracontaining products
• 10 cases with re-formulated product
• 3 literature reports of 4 patients with
acute liver injury
Evidence
• 67% (n=12) were 20-40 years old
• Outcomes
– Recover: 11
– Liver failure: 2
– Unknown: 5
• 10 cases provided liver function tests
• 9 negative drugs, autoantibodies,
viruses
Evaluation
• Adverse events
– Temporal relationship of exposure to
injury
– Exclusion of other causes of liver disease
– Resolution upon product discontinuation
• Unknowns
– Responsible ingredient(s)?
– Dose-response?
• Studies of benefit not compelling
Soladek™
• Received seven reports of serious health problems occurring in
consumers using the product. The problems include decreased
renal function, elevated levels of calcium in the blood, fatigue, heart
arrhythmia, vomiting, and diarrhea.
• Symptoms of vitamin D toxicity include weakness, fatigue,
headache, nausea, vomiting, diarrhea, changes in mental status,
increased blood pressure, abnormal heart rate or rhythm, kidney
damage, and coma.
• Symptoms of vitamin A toxicity include anemia, anorexia, alopecia,
joint pain, bone weakness, bulging eyes, liver abnormalities, and
birth defects.
• Other “related” products
Other considerations
• Contaminants
– Intentional
– Unintentional
Harm Removal Business
• What are the major non-compliance
problems in the Dietary Supplement
Industry?
• How does the agency address them?
Defining the problem encompassing
AERs
Invisible Harms - are those which are difficult to
discern and analyze because they tend to be
under-reported
Conscious Opponents - agencies are confronted
with individuals or groups of individuals who are
engaged in creating a harm (i.e. tainted products)
Catastrophic harms - relatively unlikely harmful
events that produce enormous levels of
victimization
Character of Harms – M. Sparrow
Solutions
• Responsibility (who is?)
• Process Improvement (which one to
choose?)
Let’s go to the numbers
• Estimates of 1600-2800 DS firms
• 55,000 + products on the market
Calendar Year SAER totals
3249
3500
3000
2364
2500
2000
1500
1000
1216
890
890
2008
2009
Mandatory SAERs
500
0
2010
year
2011
2012
257 unique firms have reported Mandatory
SAERs since law went into effect
120
120
115
119
119
110
# of firms that
submitted a
mandatory AER
105
106
100
101
95
90
2008
2009
2010
2011
2012
1000
929
900
800
698
700
673
600
500
387
400
300 206
200
276
339
217 186
188 154
160
97
100
0
0
2008
0
2009
2010
2011
2012
firm A
firm B
no name reported
3500
3249
3000
2364
2500
1941
2000
1500
1000
500
1216
890
2 firms and unknown
Cumulative total
1361
890
394
314
2008
2009
500
0
2010
2011
2012
Examples of Under-reporting
Quincy Bioscience WL
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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.
Evidence of Under-reporting
• BioSan, Nordimex and Theta Brothers
WLs all cited 403(y)
• ATF/Made Injunction cited a failure to
send in SAERs
• Import refusals for 403(y)
• Recent OIG exam cited that approx 30%
of the firms in it’s sample didn’t have a
label compliant with 403(y)
Triggers
• Safety/Unsafe
• Statutory Obligations
• Common ground
Serious Adverse Event Reporting
• SAER Challenges for addressing Safety
– (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 does the Agency use SAERs
to determine acute, chronic and “mixed/combination”
risk to supports the basis for causality, when and where
appropriate? What are the triggers?
• Because of these limitations, SAE reports
are primarily useful for hypothesis
generating, rather than hypothesis testing
Safety Triggers for Thought
• Specific to a Product or Ingredient
• Labeling/Use Directions/Normal
Conditions of Use
• Pathology of Events
• Mechanism
• Food Regulatory Paradigm different than
Rx (i.e. Δ in application of numerator and
denominators)
Statutory triggers
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 cGMPs regarding product
complaints, what might this mean for other
requirements?
• Assessment of a firm’s capabilities
Some of FDA’s Expectations
Labels that meet 403(y)
SOP’s for AERs and product complaints & related documents/records
Training of those that handle AERs
How does the firm obtain follow-up?
Has the firm ever sent SAERs to FDA? Have you ever received an AER?
Does the firm monitor indirect sources of information on AERs? (e.g. social
media, news)
How does the firm apply medical judgment for those reports they chose not to
submit?
How are calls & mailed AERs routed if a 24-hr line isn’t available?
Other expectations
• By rule of construction – SAERs aren’t
causal - a failure to submit or a lack of
submitting SAERs doesn’t make a product
safe!
• Is your system making your product
“better”?
• Would you know it if it wasn’t?
The take home
• Safety for dietary supplements is a complex picture
• Under-reporting is substantial – this must be remedied
via responsibility and improved processes
• Expectations of reporting system may also be flawed, a
system that tests hypotheses has limited value, one that
develops new ones is preferable
• The agency will be taking more action in this area,
triggered by “both” issues
• 341 inspections in FY 2012 are there other ways of
obtaining a look into AERs?