U.S. FDA Perspective on Food Supplements/TM

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U.S. FDA Perspective on Food Supplements/TM

• IKHLAS A. KHAN
• National Center for Natural Products Research,
  Department of Pharmacognosy and Research
  Institute of Pharmaceutical Sciences, School of
  Pharmacy,
• The University of Mississippi

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• What is a dietary supplement in the US?
• As defined by the United States Congress in the
  Dietary Supplement Health and Education Act
  (http//www.fda.gov/ opacom/laws/dshea.htmlsec3),
  which became law in 1994, a dietary supplement
  is a product (other than tobacco) that
• is intended to supplement the diet
• contains one or more dietary ingredients
  (including vitamins, minerals, herbs or other
  botanicals, amino acids, and other substances)
  or their constituents
• is intended to be taken by mouth as a pill,
  capsule, tablet, or liquid
• and is labeled on the front panel as being a
  dietary supplement.

http//ods.od.nih.gov/factsheets/DietarySupplement
s.asp
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What does DSHEA mean?

• Dietary supplements are regulated as foods
  within the meaning of the act.
• Does not require pre-market notification or
  registration of products, except for new dietary
  ingredients (NDI).

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Where do you want to go today?
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What is the
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Intended Use Makes a Difference
Not ingested, applied to the body
Intended use is food
Diagnose, cure, or treat a disease
FOOD
COSMETIC
DRUG
Ingested to affect structure or function of body
Ingested to supplement the diet
DIETARY SUPPLEMENT
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Under US Regulations Botanicals can be regulated
as

• Foods - conventional foods, functional foods,
  spices, dietary supplements
• Drugs - OTC, prescription
• Biologics - allergenic vaccines
• Cosmetics - shampoos
• Devices - dental alginates, poultices, adhesives

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Safety categorization plays a major role!
Food ltltltltltltltltltltltltgtgtgtgtgtgtgtgtgtgtgtgtgtDrugs
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Safety Assumptions

• Drugs - Health benefit vs. risk evaluation.
• Generally regarded as unsafe!

• Dietary supplements -Components are Generally
  Recognized as Safe (GRAS).
• GRAS Notification (www.cfsan.fda.gov/rdb/opa-gras
  .htm)

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Quality Standard Differences

• Drug
• Utilize Pharm Good Manufacturing practices (GMP)
• Main focus on consistency, potency and purity.

• DS/Foods
• Utilize Food (GMP)
• Main focus on the reduction of contaminants
  adulterants and filth.

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Drugs vs. Dietary Supplement Claims

• Drug manufacturers may claim that their product
  will diagnose, cure, mitigate, treat or prevent a
  disease.

• Dietary supplement manufacturers can not legally
  make these claims!

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What can dietary supplement manufacturers claim?

• A dietary supplement or food product may contain
  one of three types of claims
• A health claim - diets high in calcium may
  reduce the risk of osteoporosis
• A nutrient content claim - A good source of
• or A structure/function claim - calcium builds
  strong bones., antioxidants maintain cell
  integrity

(http//www.cfsan.fda.gov/dms/hclaims.html)
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Authorized health claims for DS

• NLEA Authorized Health Claims.
• The Nutrition Labeling and Education Act (NLEA)
  1990.
• Must meet a significant scientific agreement
  standard.
• Health Claims Based on Authoritative Statements.
• FDAMA - (FDA Modernization Act of 1997)
• authoritative statement from a scientific body
  of the US Government or the National Academy of
  Sciences.
• Qualified Health Claims.
• Claims that contain qualifying language to
  reflect level of scientific support and are not
  misleading to consumers.
• FDA guides http//www.cfsan.fda.gov/dms/hclmgui3.
  html

(http//www.cfsan.fda.gov/dms/hclaims.html)
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New Dietary Ingredient (NDI) Notification

• Required for all new ingredients which were not
  marketed in the US prior to October 15th 1994
  (DSHEA).
• Notifications should be submitted to FDA 75 days
  prior to marketing.
• Information must exist which establishes a
  reasonable expectation of safety for products
  containing the NDI.
• The FDA does not approve or disapprove the
  NDI rather they post objections.

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NDI Status 1995-2005
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Items that FDA Currently Enforces

• Androstenedione
• Ephedra
• Steroidal precursor substances
• Aristolochic Acid

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Guidelines for Botanical Drug Products

• FDA Published on 6/9/2006
• More information at www.fda.gov/cder/ guidance

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Botanical Drugs NDA vs. Monograph

• Botanical drugs can be developed in United States
  through
• New drug applications (NDA)
• Prescription drug
• Over-the-counter drug
• Monographs for Over-the-counter (OTC)

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Guidance Principals

• Identification of active constituents not
  essential
• Purification not required
• Chemistry/Manufacturing and Control (CMC) will be
  extended to raw materials
• Non-clinical evaluations may be reduced
• Same level of clinical efficacy/safety
  requirements as standard drugs
• In general the FDA will utilize the historical
  safety information to expedite early stage
  testing and evaluation of botanical products.

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Botanical Drug Review

• IND Safety review related to scope of the
  proposed clinical studies
• Preliminary studies (Phase I/II)
• Marketed products vs not marketed or
• Marketed with safety concerns
• Expanded studies (Phase III)
• End-of-Phase 2 meeting
• New Drug Application (NDA)
• Safety/efficacy quality and therapeutic
  consistency
• Pre-NDA meeting

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Botanical IND Considerations

• A botanical or a non-botanical IND?
• Crude extracts, partially purified fractions
• Combination of highly purified compounds from
  different plants
• Single herb or multiple-herb product
• Botanical only or botanical with other active
  components
• E.g., vitamins, minerals, animal parts

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BRT Review of Botanical INDs Based on Prior Human
Use

• Comparing the doses and durations of the
  botanical product/raw materials in IND with
  previous human uses
• Is the product/trial reasonably safe?
• Report known side effects or potential safety
  issues
• Comment on the relationship between prior human
  use and the proposed indications

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Common issues of Initial IND Submissions

• Incomplete information on raw materials
• Scientific name or botanical parts not specified
• Multiple plant species used for one botanical
  material
• Safety information gaps of botanical raw
  materials and products
• Yields of extracts from raw materials not
  provided
• Unreasonably high dose (in weight of raw herb)
• Proposed long trial duration that is not
  supported by prior human experience

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Botanical Applications to FDA (as of June 1,
2006)

• Total of 286 Applications
• 232 INDs (2/3 active not necessarily mean
  currently enrolling or treating patients)
• 54 pre-INDs
• Currently 2-3 new submissions per month
• 40 commercial, 60 research
• gt2/3 single herb, lt1/3 multiple herbs

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Increasing s of Botanical Applications to FDA
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Therapeutic Areas Covered in Applications
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Scientific Issues that Impact the Regulation of
Dietary Supplements

• GMP/GAP-related Identification/substitutions,
  purity, quality issues 
• Contaminants  chemical, filth, heavy metals,
  pesticides, microbial, sterilization techniques
• Efficacy - identification of "active" components,
  standardization issues related to products
  (markers of quality, active ingredients,
  surrogate markers, etc.)
• NDI safety issues - evidence needed to ensure
  safety
• Interactions with drugs and other dietary
  ingredients 
• Type of safety evidence needed when use expands
  beyond traditional user populations/exposures.
  (children,elderly, preg/lact women, childbearing
  age, etc.).