1. 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

2. What is a dietary supplement in the US?
As defined by the United States Congress in the Dietary Supplement Health and Education Act ( opacom/laws/dshea.html#sec3), 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.

3. 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).

4. Dietary Supplement
Food
Drug
Where do you want to go today?

5. What is the

6. “Intended” Use Makes a Difference
Not ingested, applied to the body
Diagnose, cure, or treat a disease
Intended use is food
COSMETIC
DRUG
FOOD
Ingested to affect structure or function of body
Ingested to supplement the diet
DIETARY
SUPPLEMENT

7. 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

8. Safety categorization plays a major role!
Food <<<<<<<<<<<<>>>>>>>>>>>>>Drugs

9. Safety Assumptions Drugs - Health benefit vs. risk evaluation.
Generally regarded as unsafe!
Dietary supplements -Components are Generally Recognized as Safe (GRAS).
GRAS Notification (

10. 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.

11. 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!

12. 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” (

13. “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 (

14. 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.

15. NDI Status

16. Items that FDA Currently Enforces
Androstenedione
Ephedra
Steroidal precursor substances
Aristolochic Acid

17. Guidelines for Botanical Drug Products
FDA Published on 6/9/2006
More information at guidance

18. 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)

19. 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.

20. 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

21. 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

22. 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

23. 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

24. 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
>2/3 single herb, <1/3 multiple herbs

25. Increasing #’s of Botanical Applications to FDA

26. Therapeutic Areas Covered in Applications

27. 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.).