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Safety of Dietary Supplements

Comments by Daniel Fabricant, Ph.D.

Director, Division of Dietary Supplement Programs,

ONLDS, CFSAN

daniel.fabricant@fda.hhs.gov

February 8, 2013

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• 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

• Liver injury AEs provided the signal• Sept. 2008: Physicians contact FDA• CAERS search ID’d 18 cases• 8 cases were 2002-04 for ephedra-

containing 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

890 8901216

2364

3249

0

500

1000

1500

2000

2500

3000

3500

2008 2009 2010 2011 2012

year

Calendar Year SAER totals

Mandatory SAERs

257 unique firms have reported Mandatory SAERs since law went into effect

106

101

120 119 119

90

95

100

105

110

115

120

2008 2009 2010 2011 2012

# of firms thatsubmitted amandatory AER

206

0

188 154

0

160217

97186

387

698

276

673

929

339

0

100

200

300

400

500

600

700

800

900

1000

2008 2009 2010 2011 2012

firm A

firm B

no name reported

394

890

314

890

500

1216 1361

2364

1941

3249

0

500

1000

1500

2000

2500

3000

3500

2008 2009 2010 2011 2012

2 firms and unknown

Cumulative total

Examples of Under-reporting

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.

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 ExpectationsLabels 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?