STATE OF CALIFORNIA--HEALTH AND HUMAN SERVICES AGENCY GRAY DAVIS,
*Governor*

**DEPARTMENT OF HEALTH
SERVICES**![](media/image1.png){width="0.7590277777777777in"
height="0.8645833333333334in"}

714/744 P STREET

P. O. Box 942732, MS-357

Sacramento, CA 94234-7320

\(916\) 445-2263

\(916\) 322-6326 FAX

August 20, 1999

# Docket No. 99N-1174

Dockets Management Branch (HFA-305)

Food and Drug Administration

5630 Fishers Lane, Room 1061

Rockville, MD 20852

\`FDA Dockets@bangate.fda.gov\'

Subject: Written comments to Docket No. 99N-1174

Enclosed are written comments prepared by the California Department of
Health Services, Food and Drug Branch (FDB) to the seven questions posed
by the U. S. Food and Drug Administration (FDA) as part of FDA's effort
to develop an overall strategy for achieving effective regulation of
dietary supplements.

FDB appreciates the opportunity to comment on theses questions. Please
call Susan Loscutoff, Ph.D., FDB Staff Toxicologist, at (916) 327-8039
with any questions or comments.

Sincerely,

### Original signed by

*James M. Waddell, Acting Chief*

*Food Safety Section, for*

Stuart E. Richardson, Jr., M.P.H., Chief

Food and Drug Branch

Enclosure

Following are written comments prepared by the California Department of
Health Services, Food and Drug Branch (FDB) to the seven questions posed
by the U. S. Food and Drug Administration (FDA) as part of FDA's effort
to develop an overall strategy for achieving effective regulation of
dietary supplements.

1.  **In addition to ensuring consumer access to safe dietary
    supplements that are truthfully and not misleadingly labeled, are
    there other objectives that an overall dietary supplement strategy
    should include?**

> To ensure that consumers have access to safe dietary supplements, FDB
> believes that FDA needs to improve its system for capturing adverse
> reactions, also described as adverse events. Top FDA officials and the
> President's Commission on Dietary Supplement Labels recently described
> the importance of adverse event reports in ensuring the safety of
> dietary supplements and the need to improve the existing system for
> capturing these events. The 1997 report of the President's Commission
> on Dietary Supplement Labels, in its guidance on the safety of dietary
> supplements, advised FDA, the dietary supplement industry, the
> scientific community, and consumer groups to work together to improve
> the post‑marketing surveillance systems for dietary supplements.
> Dr. Jane Henney, FDA's Commissioner, in her March 25, 1999, statements
> before the House Committee on Government Reform, described FDA's
> reliance on adverse event reports, among other things, in taking
> action against unsafe dietary supplements. Mr. Joseph Levitt, Director
> of FDA's Center for Food Safety and Applied Nutrition, in his May 27,
> 1999, comments before the same committee described FDA's Office of
> Special Nutritionals, Adverse Events Monitoring System as a critical
> part of FDA's ability to meet the consumer protection provisions of
> DSHEA, but Mr. Levitt acknowledged that there are enhancements to this
> system that certainly should occur.

The Office of Special Nutritionals, Adverse Events Monitoring System was
established in 1993. As of October 20, 1998, the Special Nutritionals
Web Report listed 2621 adverse events from 3451 products. By comparison,
in FY 1998, more than 230,000 reports of suspected adverse events were
received by FDA\'s adverse event reporting system for drugs and
therapeutic biological products. In one year, FDA received roughly
100-times more reports of adverse events for drugs and therapeutic
biological products than it received in five years for dietary
supplements. Unfortunately the 2621 reports of adverse events from
dietary supplements in five years do not necessarily mean that dietary
supplements are that much safer than drugs. These 2621 reports most
likely represent a vast under-reporting of the actual adverse events
experienced by consumers of dietary supplements.

Why the under-reporting?

The current system for reporting adverse events from dietary supplements
is unknown to most consumers and, from FDB's experience, to many health
professionals, and is not routinely used by agencies like poison control
centers, emergency rooms, and state and county health departments that
regularly get adverse event reports for dietary supplements. The nightly
news and many other sources of consumer information comment repeatedly
that FDA does not regulate dietary supplements. Some may even view the
FDA disclaimer, "This statement has not been evaluated by the Food and
Drug Administration" as further evidence that it is not important to
report adverse events to the FDA. Assuming consumers or health
professionals have overcome these disincentives, once they reach the
MedWatch page on FDA's website, completing the form is cumbersome and
sets a very high standard, in FDB's opinion too high, for the types of
adverse events FDA is currently trying to capture: death,
life-threatening situations, admission to a hospital or a longer than
expected hospital stay, permanent disability, birth defects, or the need
for medical or surgical care to prevent permanent damage.

> FDB believes that most adverse events from dietary supplements are
> likely to be mild and reversible when the supplement is discontinued
> (e.g., palpitations from ephedrine‑containing supplements, dependence
> on melatonin for sleep, tingling fingers and bloody urine from ginkgo
> biloba), but some events can be life‑threatening (e.g., coronary
> vasospasm and hemorrhagic stroke). Mild adverse events may indicate
> physiologic responses that foretell serious consequences and capturing
> mild adverse events is needed to evaluate the safety of dietary
> supplements. An improved surveillance system to capture all adverse
> events could lead to better public health protection through 1)
> product removal for unsafe products, 2) formulation requirements for
> products containing biologically active constituents that pose a
> health risk above certain levels, 3) additional labeling requirements
> including limitations for use and warnings to high risk groups, and 4)
> public education efforts.

How can the current adverse events monitoring system for dietary
supplements be improved?

FDB believes that a system, like that used for drugs and therapeutic
biological products, that relies on manufacturers and distributors to
collect adverse event reports and forward them to FDA, is not likely to
work for dietary supplements. FDB recalls a firm that reported no
complaints from consumers of its ephedrine-containing supplement. A
subsequent inspection of the firm found several hundred letters from
consumers returning this supplement and requesting a refund. Maybe
requests for refunds are not complaints, but FDA cannot be assured of
getting reliable information if firms decide for themselves what
constitutes a complaint or an adverse event. In addition, in California,
many firms manufacturing or distributing dietary supplements are small
and staffed by individuals with limited English. These firms do not have
the resources to accurately record information about adverse events for
transmittal to FDA.

FDB believes that FDA needs to increase its partnership activities with
poison control centers, emergency rooms, and state and county health
departments so that all adverse event reports for dietary supplements
received by these agencies are included in the Special Nutritionals
Adverse Events Monitoring System database. Because of issues of patient
confidentiality and the poison control centers' requirements for prompt
follow‑up, FDA may need to contract with the American Association of
Poison Control Centers to obtain periodic updates of the Poison Control
Centers' database.

In addition, FDA and the American Association of Poison Control Centers
need to work together to develop better categories for recording
consumer contacts for dietary supplements. The Association's 1997 annual
report lists one category for food products/food poisoning, one category
for dietary supplements/homeopathics, 24 categories of multivitamins
with and without iron and fluoride, and 8 categories of individual
vitamins. This report lists more than 48,000 consumer contacts for the
32 categories of vitamins with approximately 1700 of these contacts
reporting adverse reactions, 23 of them serious. Developing categories
for dietary supplements is likely to be more difficult than for other
products in the Association's database because many dietary supplements
are combinations of very different ingredients including vitamins,
minerals, herbs, extracts of animal tissue, and diverse biologically
active chemicals such as CoQ~10~, creatine, DHEA, and androstenedione,
to name a few. Single‑ingredient products could easily be categorized by
ingredient. Combination products could be categorized based on the
nature of the ingredients: herbals, herbals plus vitamins and/or
minerals, herbals plus non‑vitamin ingredients, and non‑vitamin,
non-herbal combinations. For combination products, any categorization
needs to identify the primary ingredient and hopefully could identify at
least the three to five main ingredients.

FDA should not rely solely on its existing system and improved
partnering with poison control centers, emergency rooms, and state and
county health departments for capturing adverse events from dietary
supplements. Consumers experiencing adverse events from dietary
supplements that do not think to contact one of these entities need to
have someplace to call. FDB recommends that all dietary supplements
include on the label an 800 number and a website for contacting either
FDA's Special Nutritionals Adverse Events Monitoring System or the
American Association of Poison Control Centers. Once consumers make this
contact, the interaction needs to be easy, informative, and quick. The
800 number could be answered electronically by a voice transcribing
system that asks and records answers to specific questions in a
retrievable, searchable database. The website could ask consumers to
post answers to the same questions online and record answers in the same
database as the calls. All contacts should be triaged to allow FDA or
the Association to quickly capture and follow-up on potentially
life‑threatening adverse events like the cardiac disturbances caused by
*Digitalis lanata*, mistakenly present in a dietary supplement labeled
to contain plantain. From FDB's experience, any system allowing
consumers to report adverse events online should not use Portable
Document Format (PDF) files because consumers attempting online
reporting may not have the Adobe Acrobat reader needed for PDF files,
may not want to take the time to download the reader, and may find it
cumbersome to navigate through PDF files.

FDB recognizes that a label requirement for an 800 number and website
for reporting adverse events may be considered by some to be beyond the
scope of the Dietary Supplement Health and Education Act (DSHEA). Since
manufacturers of dietary supplements have minimal requirements for
demonstrating the safety of their products and FDA has the burden of
showing that dietary supplements are unsafe, FDB believes that the lack
of provisions for capturing adverse events from dietary supplements
represents a serious deficiency in DSHEA. The 2621 adverse events
reported to FDA in five years for dietary supplements compared with the
230,000 adverse events reported to FDA in one year for drugs and
therapeutic biological products and the 1700 adverse reactions in one
year reported to poison control centers for vitamins may provide impetus
to the U. S. Congress to amend DSHEA to better enable FDA to capture
adverse events from dietary supplements. In the meantime, as recommended
by the President's Commission on Dietary Supplement Labels, FDA should
work with the dietary supplement industry, the scientific community,
consumer groups, poison control centers, and perhaps the States, to
improve the adverse events monitoring system for dietary supplements.

2.  **Are the criteria for prioritizing the tasks within the supplement
    strategy appropriate? Which specific tasks should FDA undertake
    first?**

# ***"A" list***

> ***1.Ephedra: Complete current stage of rulemaking addressing dietary
> supplements that contain ephedrine alkaloids.***
>
> ***2.New Dietary Ingredients: Review premarket notifications for
> supplements containing new dietary ingredients within statutory
> timeframes (75 days).***
>
> ***3.Nutrient Content/Health Claims: Publish a proposed rule on the
> applicability to dietary supplements of the FDA Modernization Act
> provisions on nutrient content/health claim notifications based on an
> authoritative statement.***
>
> ***4.Overall Strategy: In conjunction with other involved Agency
> units, and providing an opportunity for stakeholder input, develop an
> overall strategy for achieving effective regulation of dietary
> supplements under the Dietary Supplement Health and Education Act
> (DSHEA). The strategy shall address all elements of the dietary
> supplement program, including:***

-   ***boundaries between a dietary supplement and a conventional food,
    between a dietary supplement and a drug, and between a dietary
    supplement and a cosmetic product;***

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-   ***claims;***

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-   ***good manufacturing practices;***

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-   ***adverse event reporting, review, and follow-up;***

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-   ***laboratory capability;***

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-   ***research needs;***

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-   ***enforcement; and***

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-   ***resource needs.***

> ***5.Stakeholder Outreach: In addition to obtaining input on overall
> strategy development, enhance outreach efforts to stakeholders to
> assure effective communication.***
>
> ***6.Citizen Petition: In conjunction with ORA, respond to citizen
> petition 98P-0509 regarding FDA's jurisdiction over publications
> associated with dietary supplements.***
>
> ***\"B\" List***
>
> ***1.Elevate the priority of field assignments on dietary supplements,
> such as dieter's teas and folic acid-containing products.***
>
> FDB believes that improving "**adverse event reporting, review, and
> follow-up"** should be given a much higher priority and be one of the
> first tasks undertaken by FDA.
>
> The current strategy addresses claims provided for by the
> Authoritative Bodies provisions of the FDA Modernization Act, but does
> not address the issue of claims, (i.e., "Statements of Nutritional
> Support" provided for in DSHEA). The Statements provided for in DSHEA
> fall within a section of the Food, Drug, and Cosmetic Act that
> preempts States from making independent determinations of allowable
> claims. For States to be effective partners with FDA in assuring that
> statements for dietary supplements are truthful, not misleading, and
> do not cause dietary supplements to be categorized as drugs, FDA needs
> to make it a priority to finalize its proposed rule for statements on
> dietary supplements, *Federal Register,* April 29, 1998.

3.  **What factors should FDA consider in determining how best to
    implement a task (i.e., use of regulations, guidance, etc.)?**

> In determining whether to use regulations or guidance documents, FDA
> needs to consider:

-   public health impact -- tasks with substantial public health impact
    require market uniformity and effective FDA enforcement which likely
    would require regulations rather than guidance documents

-   the need for and importance of public comments that are required for
    regulations, but may not be for guidance documents,

-   the importance of market uniformity to assure consumer access to
    safe dietary supplements that are truthfully and not misleadingly
    labeled -- regulations assure market uniformity, guidance documents
    do not

-   timeliness and workload -- regulations are time and labor intensive,
    guidance documents are likely to be less burdensome to FDA

-   the potential effectiveness of FDA's enforcement efforts for
    products found to be out of compliance -- regulations are readily
    enforceable, guidance documents may be subject to interpretation

-   stakeholder's access to guidance documents -- regulations can be
    accessed in several different ways, FDB has had problems locating
    some of FDA's guidance documents

4.  **What tasks should be included under the various dietary supplement
    program elements in the CFSAN 1999 Program Priorities document?**

-   **Good Manufacturing Practices** -- GMP's should specify product
    standards including standards for the quantity of ingredients and
    "active" ingredients (e.g., hypericin in St. John's Wort)

## Laboratory Capability -- FDA should work with industry laboratories to develop validated laboratory procedures for measuring the quantity of all ingredients, including "active" ingredients like hypericin in St. John's Wort, identified on the labels of dietary supplements

-   **Research Needs** -- FDA should work with industry to develop
    appropriate warnings and encourage the use of these warnings on
    dietary supplements containing ingredients that may pose a health
    risk to consumers with an existing medical condition or taking
    certain prescription or over-the-counter drugs

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-   **Resource Needs** -- FDA may need to petition congress to obtain
    the resources to improve its adverse event reporting system

##  

5.  **Are there current safety, labeling, or other marketplace issues
    that FDA should address quickly through enforcement actions to
    ensure, for example, that consumers have confidence that the
    products on the market are safe and truthfully and not misleadingly
    labeled?**

> There is at least one chemical, 4-hydroxyvalerate (4-methyl gamma
> hydroxybutyrate), and there may be more, with biological effects
> similar to gamma hydroxybutyrate (GHB) and gamma butyrolactone (GBL).
> Immediately following FDA's recent action against GBL, FDB received a
> call asking whether 4‑hydorxyvalerate was illegal. FDB recommends that
> FDA investigate chemicals related to GHB and GBL and take preemptive
> action to assure that they do not enter the marketplace.

6.  **Toward what type or area of research on dietary supplements should
    FDA allocate its research resources?**

> Last summer's publicity that Mark McGwire was taking androstenedione
> raises concern that teens may start using this substance and other
> steroid hormone precursors like dehydroepiandrosterone (DHEA) for
> conditioning and to improve muscle mass. Additional research is needed
> on the effects of supplements of steroid hormone precursors on
> endogenous hormone levels and how changes in supplement‑induced
> hormone levels could effect the long‑term health of consumers. Since
> endogenous hormone levels effect an individual\'s response to these
> precursor substances, information is needed not only for teens, but
> for adult men, and pre- and post‑menopausal women. With this research,
> FDA could assure that supplements containing steroid hormone
> precursors are safe and, if necessary, labeled with appropriate
> warnings.

7.  **Given FDA's limited resources, what mechanisms are available, or
    should be developed, to leverage FDA's resources to meet effectively
    the objective of the strategy?**

FDA may be able to leverage its resources by improving its partnerships
with other agencies involved with assuring that dietary supplements are
safe and truthfully labeled including:

-   state and county health departments --

-   rapid communication of voluntary recalls and product alerts to all
    state health departments so states could work with FDA to assure
    that affected products are removed from the marketplace. States may
    alert FDA of additional violative products.

-   encourage state and county health departments to report to FDA all
    adverse reactions from dietary supplements

-   publish disallowed "structure/function" claims on FDA's website so
    states can take consistent actions against products making
    inappropriate claims

-   American Association of Poison Control Centers --

-   work with this Association to improve categories for recording
    contacts for dietary supplements

-   provide a way for FDA to get periodic updates of the Association's
    database

-   emergency rooms --

-   partner with the Consumer Product Safety Commission so that The
    National Electronic Injury Surveillance System (NEISS) captures
    patients treated in emergency rooms for adverse reactions from
    dietary supplements, including victims of rape where the victim may
    have been impaired after using or being given a supplement
    (e.g., gamma hydroxybutyrate)

-   provide a way for FDA to get periodic updates of the NEISS database

-   Federal Trade Commission (FTC) -- work with the Commission to assure
    consistency in regulatory actions regarding labeling (FDA) and
    advertising (FTC) of dietary supplements

-   consumer groups like the Center for Science in the Public Interest
    -- encourage consumer groups to inform constituents to contact FDA
    if they have experienced an adverse reaction from a dietary
    supplement

-   trade associations representing the dietary supplement industry
    (e.g., the Council for Responsible Nutrition, the American Herbal
    Products Association, and the National Nutritional Foods
    Association) -- work with these associations to

-   develop and publish validated laboratory procedures for measuring
    the quantity of all ingredients in dietary supplements

-   develop with these associations and encourage association members to
    use appropriate warnings on dietary supplements containing
    ingredients that may pose a health concern for some consumers

Improved partnering with these entities may give FDA leverage to
petition the U. S. Congress for additional resources to assure that
dietary supplements are safe and truthfully labeled.

Butler, Jennie C

From: Loscutoff, Susan \[SLoscuto@dhs.ca.gov\]

Sent: Friday, August 20, 1999 1:19 PM

To: \'Dockets\'; Waddell, Jim; Richardson, Stuart; Loscutoff, Susan

Subject: Docket 99N-1174

Attached are comments from the California Department of Health Services,

Food and Drug Branch, on Docket 99N-1174, on how the U. S. Food and Drug

Administration can develop an overall strategy for achieving effective

regulation of dietary supplements.

\<\<fdasupplt.doc\>\> \<\<fdasupp.doc\>\>

Susan Loscutoff, Ph.D., D.A.B.T.

sloscuto@dhs.ca.gov \<sloscuto@dhs.ca.gov\>

P.O. Box 942732

Sacramento, CA 94234-7320

\(916\) 327-8039

\(916\) 322-6326 FAX