U.S. FDA Perspective on Food Supplements/TM

U.S. FDA Perspective on Food Supplements/TM

IKHLAS A. KHANNational Center for Natural Products Research,

Department of Pharmacognosy and Research Institute of Pharmaceutical Sciences, School of Pharmacy,

The University of Mississippi

IKHLAS A. KHANNational 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?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 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).

Where do you want to go today?

Food Drug

Dietary Supplement

What is theWhat is the What is theWhat is the

“Intended” Use Makes a Difference“Intended” Use Makes a Difference

DIETARY DIETARY SUPPLEMENTSUPPLEMENT

Not ingested, applied to the body

Intended use is food

Diagnose, cure, or treat a disease

Ingested to affect structure or

function of body

Ingested to supplement

the diet

FOODFOODCOSMETICCOSMETIC DRUGDRUG

Under US Regulations Botanicals can be regulated as:

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

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!

Safety categorization plays a major role!

National Center for National Center for Natural Products ResearchNatural Products Research

Food <<<<<<<<<<<<>>>>>>>>>>>>>Drugs

Safety AssumptionsSafety Assumptions

Drugs - Health benefit vs. risk evaluation.

Generally regarded as unsafe!

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)

Dietary supplements -Components are Generally Recognized as Safe (GRAS).

GRAS Notification (www.cfsan.fda.gov/~rdb/opa-gras.htm)

Quality Standard DifferencesQuality Standard Differences

Drug Utilize Pharm Good

Manufacturing practices (GMP)

Main focus on consistency, potency and purity.

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.

DS/Foods Utilize Food (GMP) Main focus on the

reduction of contaminants adulterants and filth.

Drugs vs. Dietary Supplement ClaimsDrugs vs. Dietary Supplement Claims

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

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!

Dietary supplement manufacturers can not legally make these claims!

What can dietary supplement manufacturers claim?

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”

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 “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

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) NotificationNew 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.

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 1995-2005NDI Status 1995-2005

0

10

20

30

40

50

60

1995 1997 1999 2001 2003 2005

No ObjectionObjection

Items that FDA Currently Enforces Items that FDA Currently Enforces

Androstenedione Ephedra Steroidal precursor substances Aristolochic Acid

Androstenedione Ephedra Steroidal precursor substances Aristolochic Acid

Guidelines for Botanical Drug ProductsGuidelines for Botanical Drug Products

FDA Published on 6/9/2006

More information at www.fda.gov/cder/ guidance

FDA Published on 6/9/2006

More information at www.fda.gov/cder/ guidance

Botanical Drugs NDA vs. MonographBotanical 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)

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 PrincipalsGuidance Principals

Identification of active constituents not essentialIdentification of active constituents not essential Purification not requiredPurification not required Chemistry/Manufacturing and Control (CMC) will Chemistry/Manufacturing and Control (CMC) will

be extendedbe extended to raw materialsto raw materials Non-clinical evaluations may be reducedNon-clinical evaluations may be reduced Same level of clinical efficacy/safety requirements Same level of clinical efficacy/safety requirements

as standard “drugs”as standard “drugs” In general the FDA will utilize the ‘historical’ In general the FDA will utilize the ‘historical’

safety information to expedite early stage testing safety information to expedite early stage testing and evaluation of botanical products.and evaluation of botanical products.

Identification of active constituents not essentialIdentification of active constituents not essential Purification not requiredPurification not required Chemistry/Manufacturing and Control (CMC) will Chemistry/Manufacturing and Control (CMC) will

be extendedbe extended to raw materialsto raw materials Non-clinical evaluations may be reducedNon-clinical evaluations may be reduced Same level of clinical efficacy/safety requirements Same level of clinical efficacy/safety requirements

as standard “drugs”as standard “drugs” In general the FDA will utilize the ‘historical’ In general the FDA will utilize the ‘historical’

safety information to expedite early stage testing safety information to expedite early stage testing and evaluation of botanical products.and evaluation of botanical products.

Botanical Drug ReviewBotanical 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

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 ConsiderationsBotanical 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

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

BRT Review of Botanical INDs Based on Prior Human Use

Comparing the doses and durations of the Comparing the doses and durations of the

botanical product/raw materials in IND with botanical product/raw materials in IND with

previous human uses previous human uses Is the product/trial reasonably safe?Is the product/trial reasonably safe?

Report known side effects or potential safety issuesReport known side effects or potential safety issues

Comment on the relationship between prior human Comment on the relationship between prior human

use and the proposed indicationsuse and the proposed indications

Comparing the doses and durations of the Comparing the doses and durations of the

botanical product/raw materials in IND with botanical product/raw materials in IND with

previous human uses previous human uses Is the product/trial reasonably safe?Is the product/trial reasonably safe?

Report known side effects or potential safety issuesReport known side effects or potential safety issues

Comment on the relationship between prior human Comment on the relationship between prior human

use and the proposed indicationsuse and the proposed indications

Common issues of Initial IND SubmissionsCommon 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

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)

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

Total of 286 ApplicationsTotal of 286 Applications 232 INDs (2/3 active; not necessarily mean currently 232 INDs (2/3 active; not necessarily mean currently

enrolling or treating patients);enrolling or treating patients); 54 pre-INDs 54 pre-INDs

Currently 2-3 new submissions per monthCurrently 2-3 new submissions per month 40% commercial, 60% research40% commercial, 60% research >2/3 single herb, <1/3 multiple herbs>2/3 single herb, <1/3 multiple herbs

Total of 286 ApplicationsTotal of 286 Applications 232 INDs (2/3 active; not necessarily mean currently 232 INDs (2/3 active; not necessarily mean currently

enrolling or treating patients);enrolling or treating patients); 54 pre-INDs 54 pre-INDs

Currently 2-3 new submissions per monthCurrently 2-3 new submissions per month 40% commercial, 60% research40% commercial, 60% research >2/3 single herb, <1/3 multiple herbs>2/3 single herb, <1/3 multiple herbs

Increasing #’s of Botanical Applications to FDAIncreasing #’s of Botanical Applications to FDA

0

20

40

60

80

100

120

1982-89 1990-94 01/95-07/00

08/00-05/04

06/04-05/06

Botanical Applications 1982-2006

Annual Ave

Period Total

Therapeutic Areas Covered in ApplicationsTherapeutic Areas Covered in Applications

0102030405060

Botanical Applications by Therapeutic Classes

pIND

IND

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.).

Scientific Issues that Impact the Regulation of Dietary Supplements

Scientific Issues that Impact the Regulation of Dietary Supplements