**[Office of Research Oversight (10R)]{.underline}**

Bi-Monthly Teleconference

Wednesday, January 14, 2004, 12 noon to 12:50 pm EST

[ORO Staff participating:]{.smallcaps}

+-----------------------+----------------------------------------------+
| > [ORO                | [ORO Regional Offices]{.underline}           |
| > Head                |                                              |
| quarters]{.underline} |                                              |
+-----------------------+----------------------------------------------+
| > Dr. David Weber     | Northeastern (Boston) -- Richard D'Augusta   |
+-----------------------+----------------------------------------------+
| > Priscilla Craig     | Southern (Atlanta) -- Dr. David Miller       |
+-----------------------+----------------------------------------------+
| > Dr. Joan Porter     | Midwestern (Chicago) -- Dr. Karen Smith      |
+-----------------------+----------------------------------------------+
| > Lisa Franklin       | Mid-Atlantic (Washington, DC) -- Dr. Min-Fu  |
|                       | Tsan                                         |
+-----------------------+----------------------------------------------+
| > Paula Squire        | Western (Loma Linda) -- Dr. Paul Hammond     |
| > Waterman            |                                              |
+-----------------------+----------------------------------------------+
| > Shannon Williams    |                                              |
+-----------------------+----------------------------------------------+

[Introduction (Dr. David Weber)]{.underline}:

In his introduction, Dr. Weber welcomed everyone to the bimonthly ORO
teleconference call. Dr. Weber then introduced the speaker, Lori A.
Love, MD, PhD, Senior Advisor for Clinical Science, Office of Regulatory
Affairs, Food and Drug Administration. Dr. Love's topic is "Dietary
Supplements Compliance Issues." A set of PowerPoint slides on issues
related to supplements included in the teleconference announcement,
served as background information for the talk. In addition to the
PowerPoint presentation, Dr. Love also supplied an FDA guidance document
to serve as an additional resource on supplements and compliance issues
related to their use in research.

These teleconferences are usually recorded and documented by notes taken
directly from this recording of the speaker's presentation.
Unfortunately, due to technical reasons, the recording of this
teleconference was not useable. As a result, notes for this
teleconference were constructed from the PowerPoint presentation,
"Dietary Supplements: Safety and Regulatory Concerns" (Lori A. Love, MD,
PhD), and guidance document.

In her talk, Dr. Love discussed two main topics related to supplements:

1\. Dietary Supplement Research Compliance - The use of and claims made
about a product determine whether it should be treated as supplement or
come under the drug regulations. If a dietary supplement product is used
in clinical research, under certain conditions an IND might be
necessary.

2\. Supplements Safety - Supplements are not without side effects and
can interact with other medications, even when they are being used
simply as indicated or labeled.

[Compliance Issue:]{.underline} ["Dietary Supplements" in Research; When
is an IND Needed?]{.underline}

Under the Dietary Supplement Health and Education Act (DSHEA), a dietary
supplement is defined as a product intending to supplement the diet and
containing one or more of these 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
these ingredients.

In determining whether research using such products might need an IND,
first of all, it must be decided whether the product is being used as a
supplement or a drug. The regulatory classification of the product
matters because drugs and supplements -

-   Have different regulatory requirements

-   Require different substantiation

-   Have different safety considerations

The manufacturer determines the regulatory classification of a product
by the type of claims that appear on the label and labeling (information
accompanying the product).

> By definition, a drug diagnoses, cures, mitigates, treats, or prevents
> a disease. If a product makes a "disease claim," then it is a drug
> (not a supplement). In this context, disease is defined as "...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..."

When an IND might be required is determined by how the product is used
in the clinical study -- if the substance is being used for a drug
purpose in the study (i.e., to treat, cure, mitigate, prevent or
diagnosis a disease) -- an IND is necessary. The determination of
whether an IND is required in a clinical trial does not depend on the
manufacturer's classification of the product or claims that appear on
the marketed product, but rather the intended use of the product in the
clinical study. Consequently, although a manufacturer may sell a product
as a dietary supplement, or a research sponsor may identify a product as
a "dietary supplement," an institution may determine that the product is
a drug because of claims made by the manufacturer/research sponsor or
because of the intended use of the product in the clinical study.

A product sold as a dietary supplement and promoted on its label or in
labeling as a treatment, prevention or cure for a specific disease or
condition would be considered an unapproved\--and thus illegal\--drug.
To maintain the product\'s status as a dietary supplement, the label and
labeling may not make such claims. Dietary supplements are allowed to
make claims related to an effect on structure or function of the body,
mechanisms of effect on structure/function, and general well-being.

An institution may need to examine the product claims to see if any
qualify as disease claims. There are 10 criteria in the rule governing
the labeling of supplements that can be used to determine if a statement
is a disease claim. Product claims that meet one or more of these
criteria may cause the product to be classified as a 'drug' so that
provisions of 21 CFR 312 (the IND drug regulations) apply. Do the
manufacturers of the product

1: Claim an effect on a disease or class of diseases?

> 2: Claim an effect on characteristic signs or symptoms of disease
> using scientific or lay terminology?
>
> 3: Claim an effect on a condition associated with a natural state or
> process?
>
> 4: Have an implied disease claim because of the product name,
> formulation, use of pictures, or other factors?
>
> 5: Claim that the product belongs to a class of products that is
> intended to diagnose, mitigate, treat, cure, or prevent a disease?
>
> 6: Claim it is a substitute for a product that is a therapy for a
> disease?
>
> 7: Claim to augment a therapy or drug intended to diagnose, mitigate,
> treat, cure, or prevent a disease?
>
> 8: Claim it has a role in the body\'s response to a disease or to a
> vector of disease?
>
> 9: Claim it can be used to treat, prevent, or mitigate adverse events
> associated with a therapy for a disease?
>
> 10: Otherwise suggest an effect on a disease or diseases?

If the answer to one or more of these questions is 'yes,' then the
product might be considered a drug, rather than a supplement. If
research is being done on this product, then the research would need to
be reviewed by an IRB, and may require an IND to be conducted. Dr. Love
stated that people with questions about whether a supplement could be
considered a drug and if the research might also require an IND may
e-mail her at <LLove@ORA.FDA.GOV> or call her at (301) 827-3101.

Guidance on supplements is located at

<http://www.cfsan.fda.gov/~dms/sclmguid.html>

<http://www.cfsan.fda.gov/~dms/ds-oview.html>

<http://www.cfsan.fda.gov/~dms/guidance.html>

[Safety Issue:]{.underline} [Supplements- Adverse Effects and
Interactions with Other Medications]{.underline}:

There is a common misconception that so-called "natural" products are
safe and without side effects; however, every product with known
pharmacological activity has shown adverse effects in some individuals
when studied properly. In addition, there are other safety issues
related to supplements. For this reason, it is important for physicians
to ask patients about dietary supplements and other products that they
might be using. This should be routine in every medical history.

The following are some of the safety concerns related to botanical and
other "natural" ingredients:

> • 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

Each safety issue will be discussed in turn.

-   **Product is directly harmful**

> Listed below are some of the known adverse effects of supplements

+----------------------------------+-----------------------------------+
| > ***[Adverse                    | ***[P                             |
| > Effects]{.underline}***        | roduct/Ingredient]{.underline}*** |
+==================================+===================================+
| > CVS                            | *Ephedra spp*. (ma huang)         |
|                                  |                                   |
|                                  | St. John's wort                   |
+----------------------------------+-----------------------------------+
| > CNS                            | *Ephedra spp*.                    |
|                                  |                                   |
|                                  | Germander (*Teucrium chamaedrys*) |
|                                  |                                   |
|                                  | # Valerian                        |
|                                  |                                   |
|                                  | GBL/GHB                           |
+----------------------------------+-----------------------------------+
| > Hepatotoxicity                 | Chaparral (*Larea dentate*)       |
|                                  |                                   |
|                                  | PA (*Symphytum, Senecio spp*.)    |
|                                  |                                   |
|                                  | Germander (*Teucrium chamaedrys*) |
|                                  |                                   |
|                                  | Kava kava                         |
|                                  |                                   |
|                                  | Anthraquinone laxatives (senna,   |
|                                  | cascara, aloe)                    |
|                                  |                                   |
|                                  | Vitamin A                         |
+----------------------------------+-----------------------------------+
| > Nephrotoxicity                 | Germanium                         |
|                                  |                                   |
|                                  | Aristolochia                      |
+----------------------------------+-----------------------------------+
| > Myopathy                       | L-Tryptophan/5-HTP                |
|                                  |                                   |
|                                  | Niacin                            |
+----------------------------------+-----------------------------------+
| > Coagulopathy                   | # Ginkgo biloba                   |
|                                  |                                   |
|                                  | Glucosamine/chondroitin SO~4~     |
+----------------------------------+-----------------------------------+

**Potential Problems Related to the Use of Dietary Supplements and Other
Natural Products**.

-   **The Product is adulterated or contaminated**

> • Pesticides
>
> • Microbial contamination
>
> • Molds, mycotoxins
>
> • Filth
>
> • Heavy metals:

-- Bee products contaminated with lead

• Drugs, chemicals

-- Black pearls, jin bu huan, and other "patent" medicines

• Misidentified or substituted ingredients

-- Plantain contaminated with digitalis

-   

-   **Product - product or other co-factor interactions occur that
    affect safety**

> • 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

• Increased nervous depression

> -- barbiturates with valerian
>
> -- benzodiazepines with kava
>
> •Co-factor interactions

• Co-factor interactions

> -- Pharmacogenetics
>
> -- Immunogenetics
>
> -- Age, gender or health condition

-   **The Product is substituted for a known effective therapy**

> Patients discontinue medications because they think supplement is
> adequate treatment.

### COMPLIANCE SUMMARY

Supplements in Research: When is an IND needed?

-   Based on marketing claims made by manufacturer/sponsor

-   Product claims determine regulatory class

-   Supplements may NOT make "disease claims"

-   Disease claims or disease uses may mean product considered a "drug"

-   If the product is a "drug," it may require an IND

**SAFETY SUMMARY**

Supplements have Side Effects and Can Interact with Other Medications

-   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

*[Next Teleconference]{.underline}: The next teleconference will take
place Wednesday, March 10, 2004 from 12 Noon to 12:50* *P.M. EST. (NOTE:
2nd* *Wednesday in March.) The call-in number is* *(800) 767-1750* *--
Access* *code 24088#.*