# Presentation: 078391

## Dietary Supplements: Safety and Regulatory Concerns

- Lori A. Love, M.D., Ph.D.Senior Adviser for Clinical Science
- Office of Regulatory Affairs
- Food and Drug Administration
- 5600 Fishers lane, HFC-2
- Rockville, MD  20857
- Telephone: 301-827-3684
- Fax: 301-443-6591
- Email: lori.love@fda.gov

## Botanicals & other natural products:       What kind of product?

- Main Entry: **bound·ary**Pronunciation: 'baun-d(&-)rEFunction: *noun*Inflected Form(s): *plural* **-aries**Date: 1626**:** something (as a line, point, or plane) that indicates or fixes a limit or extent
- Food vs. drug

## What Is a Food Today?Food Terminology 101

- Dietary supplements

- Medical food

- Conventional foods

- Foods for special dietary use

- Unconventional foods

- Special nutritionals

- Infant formulas

- Exempt infant formulas

- Functional foods

- Nutriceuticals

- Nutritional supplements

- Pharmafoods

- Farmaceutical

## Foods                                          Drugs

- Conventional foods

- Infant formulas

- Medical foods

- Food for special dietary use

- Dietary supplements

- Exempt infant formulas

- Functional foods
- Nutriceuticals

- R**x**
- OTC
- Biologics
- Devices

## Regulatory classification of product matters because.....

- Different regulatory requirements
- Different substantiation
- Different safety considerations

**Notes:**
The classification as to type of food product is important because...
This classification is confusing to many - how a product is marketed, as determined by its label and labeling, largely determines its regulatory class rather than the ingredients or how the consumer uses the product.

Products that make claims to treat, cure, prevent mitigate or diagnosis a disease are regulated as drugs (must be shown to be safe and effective for a particular indication prior to marketing)

## How are botanicals regulated by FDA?

- It depends on:
- how the product is marketed by the manufacturer

## Product claims  determines regulatory class

- Drug: diagnosis, cure, mitigation, treatment, or prevention of disease
- Disease claim = drug
- “damage to an organ, part, structure, or system of the body such that it does not function properly...or a state of health leading to such dysfunctioning...”

- D

- ietary

- S

- upplement

- H

- ealth and

- E

- ducation

- A

- ct

## Dietary Supplements: DSHEA Definition

- Intended to supplement the diet
- Contains one or more of the following dietary   ingredients:
- Vitamin,  mineral,  amino acid
- Herb or other botanical (not tobacco)
- "dietary substance" for use by man to supplement  the diet by increasing the total dietary intake
- Concentrate, metabolite, constituent, extract, or combination of any of the above

## Dietary Supplements under DSHEA

** **A product that is:**  **
-  Ingested in tablet, capsule, liquid, powder,  gelcap, softgel
-  Not represented as conventional food
-  Not represented as sole item of meal
-  Not represented as a total diet
-  Labeled as a dietary supplement

## Dietary Supplements under DSHEA

- Exclusions: Does not include articles that are:
- Approved new drugs, antibiotics, or biologics
- Authorized investigational new drug, antibiotic, or biologic
*UNLESS*  first marketed as a dietary supplement
- for INDs:
-  authorized
-  “substantial clinical studies” initiated
-  “existence...has been made public”

##  No pre-market registration, review, or approval by FDA
 Exempt from food additive provisions
 "Optional"  GMP regulations
FDA bares the burden of proving a dietary supplement is unsafe

-  Exempt from food additive provisions
-  "Optional"  GMP regulations
- FDA bares the burden of proving a dietary supplement is unsafe

*Dietary Supplements Post- DSHEA*

## Summary:  Current Safety Standards

| Category | Standard | Determination |
| --- | --- | --- |
| Conventional Food | Reasonable certainty of no harm | Manufacturer |
| Food additive | Reasonable certainty of no harm | FDA |
| GRAS ingredient | Reasonable certainty of no harm | Manufacturer
 |
| Old DS ingredient | No significant or unreasonable risk | Manufacturer
 |
| New DS ingredient | Sufficient evidence of no significant / unreasonable risk | Manufacturer
 |
| Drug | Safe and effective | FDA |

## FDA’s efforts on dietary supplements are focused on the postmarketing period

-  Adverse event monitoring
-  Other:
-  Product sampling
-  Scientific literature
-  Other sources
-  Compliance and enforcement

## Labeling

- In addition to setting product standards, FDA regulates the labeling of products under its jurisdiction.
- Information must be rigorously truthful, well documented, and not misleading.

## Dietary Supplement Claims

- Effect on structure or function of the body
- Mechanism of effect on structure/function
- General well-being

## Good manufacturing practices

- Purpose:  to make sure that products are manufactured to the same high standards
- Specific type depends upon product classification
- Periodic inspection of firm by ORA to evaluate compliance with GMPs.

## Adverse event reporting

- Many systems in different FDA centers
- No central system based on type of ingredients
- Adverse event report goes ultimately to Center with regulatory responsibility for the particular product

## Health Professionals

**ORA ****Illness/Injury**

**Poison Control**

**CDC**

**State Health Dept**

**USP**

**Correspondence**

**Congressionals**

**Industry**

- (phone/mail)

**Consumer**

**         **

**CDER**

**CBER**

**CFSAN**

**CDRH**

## Postmarketing Safety Considerations

- Characteristics of adverse events
- nature, severity, consequences
- Population affected
- vulnerable groups

## 
Postmarketing Safety Considerations

*Postmarketing Safety Considerations*

**Medicinal Products &**_** Special Nutritionals**_

_**Conventional Foods**_

**AE Categories:**

- high potentialmany different types

- limited, e.g.  infections,
- food sensitivities

**AE Etiologies:**

- multiple, often unknown

- microbial & allergy or sensitivity

**AE Duration:**

- often chronic

- acute, self-limited

**AE Evaluation:**

- extensive follow up & evaluation

- usually limited

##  Arsenic, lead, mercury
 Cobra venom
 Bacteria, viruses
 Insects, fungi

-  Cobra venom
-  Bacteria, viruses
-  Insects, fungi

*"Natural" Products:*

-  Hemlock
-  Digitalis
-  Taxol

## It’s all “natural”....!

-    "People can be induced to swallow anything, provided it is sufficiently seasoned with praise." Moliere (17th Century French playwright)

## "Natural" Products

-  Every product with known pharmacological activity has shown adverse effects in some individuals when studied appropriately.

## Why historical use can not be relied on to provide evidence of safety:

-  No documented systems to collect and evaluate adverse effects associated with product use
-  If you don't take a temperature, you will not find a fever!

## Why historical use can not be relied on to provide evidence of safety:

-  Different products, populations and use patterns today compared to historical use

## Comparison of historical use of botanicals to current use as dietary supplements

_***Historical Use***_

_***Current Use in the USA***_

- Category:

- Medicine

- Dietary supplement

- Selection:

- HCP prescribed

- Consumer selected

- Use:

- Respiratory disorders

- Weight loss, energy, other

- Formulation:

- HCP selected,
-  defined herbal combinations

- manufacturer selected, combinations of ingredients not used traditionally

- Duration of use:

- Short term

- Undefined, can be prolonged

-  Using Ephedra containing products as an example

_***Product:***_

##  "Natural"  					=	safe
 "Historical use" 	 		=  safe
 FDA approves/reviews these products prior to marketing 
 If one is good, more must be better

-  "Historical use" 	 		=  safe
-  FDA approves/reviews these products prior to marketing
-  If one is good, more must be better

*Common Misperceptions about Dietary Supplement/Other Natural Products:*

## Botanical and Other “Natural” Ingredients with Safety Concerns:

_***Adverse Effects***_		 _***Product / Ingredient***_
- CVS			 				*Ephedra spp.* (ma huang)
- 									St. John’s wort
- CNS			 				*Ephedra spp.,*
- 									Germander *(Teucrium chamaedrys)*
*	**	**	**	**	**	**	**	**	**Valerian*
*	**	**	**	**	**	**	**	**	*GBL/GHB

## Botanical and Other “Natural” Ingredients with Safety Concerns:

_***Adverse Effects***_		 _***Product / Ingredient***_
- Hepatotoxicity			Chaparral *(Larrea dentata),*
-  								PA *(Symphytum, Senecio spp),* 											Germander *(Teucrium  chamaedrys)*
*	**	*				Kava kava
- 						Anthraquinone laxatives  (senna, 								cascara, aloe)
- 						Vitamin A

## Botanical and Other “Natural” Ingredients with Safety Concerns:

_***Adverse Effects***_		 _***Product / Ingredient***_
- Nephrotoxicity		 	Germanium
- 									Aristolochia
- Myopathy					 L-Tryptophan/ 5-HTP
- 									Niacin
- Coagulapathy			 *Ginkgo biloba*
*	**	**	**	**	**	**	**	**	** *Glucosamine/ chrondoitin SO4

## Safety Considerations

- Product is directly harmful
- Product is adulterated or contaminated
- Product - product or other co-factor interactions occur
- Product is substituted for a known effective therapy

## Safety Concerns Because of Contaminants or Adulterants

- Pesticides
- Microbial contamination
- Molds, mycotoxins
- Filth
- Heavy metals:
- Bee products contaminated with lead
- Drugs, chemicals
- Black pearls, jin bu huan  other “patent” medicines
- Misidentified or substituted ingredients
- Plaintain contaminated with digitalis

## Product Interactions

- Increased anticoagulant effects
- NSAIDS or warfarin with white willow, garlic, ginger,  feverfew, ginkgo, or vitamin E
- Increased cardiovascular and nervous system stimulation
- Cardiac drugs, MAOI, caffeine, or cough/cold/other products with ephedra, kola, guarana, khat, or yohimbe
- MAOI, SSRI, or ß-sympathomimetics with St. John’s wort

## Product Interactions

- Increased nervous depression
- barbiturates with valerian
- benzodiazepines with kava

## Safety Concerns due to Co-factor Interactions

- Pharmacogenetics
- Immunogenetics
- Age, gender or health condition

## Ongoing Challenges in the Dietary Supplement Arena

- Ingredient and product standardization
- Ascertainment of ingredient / product effects
- Establishment of appropriate conditions of use
- Monitoring safety of products

## Help FDA in its safety mission: report adverse events:

- Mail:		via postage-paid MedWatch form
- Phone:  	1-800-FDA-1088
-  Fax:		1-800-FDA-1078
- Internet:	http://www.fda.gov.medwatch

## Information Sources:

- http://wwwfda.gov.fda
- http://www.cfsan.fda.gov/~dms/supplmnt.html
- NIH
- http://nccam.nih.gov/
- http://www.nlm.nih.gov/nccam/camonpubmed.html
- http://dietary-supplements.info.nih.gov/