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
• 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 - 3 rd 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 $40 000 $35 000 $30 000 $25 000 $20 000 $15 000 $10 000 $5 000 $0 6% 4% 2% 0% 12% 10% 8% Sales $M Growth Retail Growth Non-Retail Growth
• • • • •
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…” h ttp://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 35
21 CFR 111 Inspections*
• FY 2008 7 • FY 2009 34 • FY 2010 • FY 2011 • FY 2012 • FY 2013
(10/23/2012)
84 175 341* 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 – Total: 14 4% 341 37 * 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
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 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Infection, Inflammation, Prostate, Cancer Lower Cholesterol, Inflammation, Infection, Prostate, Immunodeficiency, Diabetes, Pain Infection, Mental Illness, Prostate, Cardiovascular, Immunodeficiency Infection, Allergy, Inflam., Addictions, Pain, Defects in Embryogenesis, Immunodef.
Lower Cholesterol, Diabetes, Inflammation, Infection, BP, Pain, Blood Flow Through Arteries Lower Cholesterol, Diabetes, Inflammation, Pain, Allergy, Infection Pain, Inflammation, Infection, Lower Cholesterol, BP, Diabetes BP, Infection, Lower Cholesterol, Pain, Inflammation, Diabetes, Allergy Infection, Lower Cholesterol, Pain, Inflammation, Diabetes, BP Lower Cholesterol, Diabetes, Inflammation, Pain, Allergy, Infection Infection, Diabetes, Lower Cholesterol, BP, Pain, Inflammation Pain, Infection, Diabetes, Inflammation, BP, Lower Cholesterol, Prostate Inflammation, Infections, Lower Cholesterol, BP, diabetes Inflammation, Diabetes, Infections, Blood Flow Through Arteries Inflammation, Pain, Infections, Diabetes, Hangover Pain, Inflammation, Diabetes 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) 42
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 43
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 2008 2009 2010 2011 Total cases by report type Mandatory 677 705 985 2019 4386 Voluntary Both voluntary and mandatory Total cases per year Deaths per year 430 581 391 430 1832 12 20 19 24 75 1119 1306 1395 2473 6293 12 24 23 32 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 had been reported to FDA or investigated by your firm.
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
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).