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

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.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. http://ods.od.nih.gov/factsheets/DietarySupplements.asp

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).

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

What is the

“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

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

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

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)

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.

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!

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)

“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)

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.

NDI Status 1995-2005

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

Guidelines for Botanical Drug Products FDA Published on 6/9/2006 More information at www.fda.gov/cder/ guidance

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)

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.

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

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

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

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

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

Increasing #’s of Botanical Applications to FDA

Therapeutic Areas Covered in Applications

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.).