Issue: 63 Page: 70-74
New Dietary Ingredients: DSHEA Provides Protection from Potentially Unsafe New Ingredients with no Prior Market History in the U.S.
by Chris Noonan, W. Patrick Noonan
HerbalGram. 2004; 63:70-74 American Botanical Council
New Dietary Ingredients: DSHEA Provides Protection from Potentially Unsafe New Ingredients with no Prior Market History in the U.S.
As the tenth anniversary of the passage of the Dietary
Supplement Health and Education Act of 1994 (DSHEA) approaches in October,
there appears to be confusion about some of the provisions of the Act regarding
the safety of dietary supplements and ingredients. A little-reported provision
of DSHEA addresses the issue of determining the safety of new dietary
ingredients. Congress inserted a provision in DSHEA that is intended to ensure
that new ingredients with no prior history of food use in the United States are
subjected to Food and Drug Administration (FDA) review regarding their relative
safety before these ingredients can be marketed in dietary supplements. —Editor
Is it better to be old or new? Most people would usually say
new. But if you asked any dietary supplement manufacturer who was about to
begin marketing a new dietary ingredient, the answer would probably be old. The
regulations for marketing old vs. new dietary supplement ingredients under the
Dietary Supplement Health and Education Act of 1994 (DSHEA) establish very
distinct mandatory requirements for both, but the requirements are far less
arduous for old or “grandfathered” ingredients. (Note: Some people in the
herbal community express a preference for the term “grandmothered” or even the
gender neutral “grandparented.”) Up to this point, many manufacturers assume
their ingredients are grandfathered because of a “long history of use” and then
proceed directly to market. However, an incorrect classification of a newly
marketed dietary ingredient can lead to many troublesome legal issues.
Under Section 8 (New Dietary Ingredient) of DSHEA, a new
dietary ingredient (NDI) means “a dietary ingredient that was not marketed in
the United States before October 15, 1994.”1 In contrast, an old
dietary ingredient (ODI) is a dietary ingredient that was lawfully marketed2
in the United States before October 15, 1994. For NDIs, Section 413 (a)(2) of
the federal Food, Drug and Cosmetic Act (FDC Act) requires that the
manufacturer or marketer notify FDA 75 days prior to the introduction of the
ingredient into the market with sufficient data to provide substantiation of
the ingredient’s general safety. For ODIs, a 75-day safety notification is not
required. The ingredient is presumed to be safe unless evidence suggests
otherwise (i.e., the ingredient is grandfathered).
In order to understand the significance of the NDI
determination, there are several terms that merit definition. The definition of
the term “lawfully” is certainly one for roundtable discussion.
According to informal FDA guidance,3 a “lawfully”
marketed dietary supplement requires the manufacturer or distributor to have
written evidence that the ingredient in question is chemically identical to a
dietary ingredient that was marketed in the U.S. before October 15, 1994.
However, FDA has indicated that some written evidence upon which the dietary
supplement industry has historically relied may not be sufficient. FDA stated
in correspondence to a manufacturer in responding to a 75-day notification that
“inclusion in a published list” is not sufficient to show an ingredient is old.4
Such lists include e.g., the American Herbal Products Association’s (AHPA) Herbs
of Commerce (1992),5 the “Old
Dietary Ingredient List” from the Utah Natural Product Alliance, and the “CRN
List of Dietary Ingredients – ‘Grandfathered’ Under DSHEA.”6
According to FDA, to meet this legal requirement a seller must be able to
demonstrate that the inclusion of the ODI in the above-referenced publications
is based on accurate and reliable evidence sufficient to support a finding that
the ingredient is old. FDA considers independent documentation that an
ingredient is old to be a product invoice, bill of lading, product label or
labeling, or a catalogue with evidence of a date to show evidence of marketing
before October 15, 1994.7
The significance of the requirement for lawfully marketing a
dietary ingredient takes on even more meaning. In one of the initial
submissions of a 75 day-notice for the ingredient stevia leaf (used as a
natural sweetener, derived from Stevia rebaudiana Bertoni Asteraceae), it
was argued that stevia was included in a number of marketed herbal products
before October 15, 1994. However, FDA took the position that because stevia was
considered to be an unlawful food additive, any marketing of the ingredient
before October 15, 1994 was unlawful and therefore did not meet the old dietary
ingredient qualification of DSHEA.8
Legal Significance of the “Prior Market Clause” of DSHEA
In the case of Pharmanex v. Shalala, the government
succeeded in convincing the court that “market as” is not the same as “sold
as.”9 It is not enough that the ingredient sold is present in food.
In this case the issue concerned the presence of the naturally-occurring
compound mevinolin, which, according to the government’s successful argument,
is chemically and therapeutically similar to
the active ingredient lovastatin found in the prescription drug Mevacor®
(Merck & Co., Whitehouse Station, NJ) in red yeast rice (Monascus
purpureus Went., Monascaceae). FDA argued
that there must be evidence that red yeast rice was actually marketed for its
lovastatin content. In other words, the food must be marketed for the presence
of the ingredient in question.
Based on this decision, FDA’s position on the DSHEA “prior
market clause” is that for a food constituent to have been marketed as a food
or dietary supplement, the manufacturer of the food containing the constituent
must have marketed or promoted the food based on the properties of the food
constituent at issue or increased or optimized the concentration at issue. For
example, it is not sufficient to show the marketing of malted barley if one is
trying to demonstrate the prior marketing of a malted barley extract ingredient.
The marketing of the source ingredient is not sufficient to prove prior
marketing of an extract of the source ingredient.3
If a seller has an ingredient that does not qualify as an
ODI, then it is subject to Section 413 of the FDC Act. Section 413 states that
a dietary supplement containing an NDI shall be deemed adulterated under
Section 402 (f) of the FDC Act unless it meets one of the following
requirements:
1. A dietary ingredient contains only dietary ingredients which have been present
in the food supply as an article used for food in a form in which the food has
not been chemically altered.
2. There is a history of use or other evidence of safety establishing that
the dietary ingredient, when used under the conditions recommended or suggested
in the labeling of the dietary supplement, will reasonably be expected to be safe;
and, at least 75 days before being introduced or delivered for introduction into
interstate commerce, the manufacturer or distributor of the dietary ingredient
or dietary supplement provides the FDA with information, including any citation
to published articles, which is the basis on which the manufacturer or distributor
has concluded that a dietary supplement containing such dietary ingredient will
reasonably be expected to be safe.
Exemptions to Preclude Filing the 75-day NDI Notice with FDA
The next consideration must be whether the ingredient in
question meets the second exemption from NDI legal status. To meet this
requirement the seller must demonstrate that the ingredient is consumed in food
in a form that has not been chemically altered.10 The question that
remains unanswered in the dietary supplement industry is—if one extracts an
ingredient from its botanical source, how much can the ingredient be
concentrated before it is chemically altered? FDA has further indicated that
even if the dietary ingredient extract was present in the food supply, the
seller must prove that the extract ingredient was present in the food supply as
an article used or marketed as a food or as an ingredient of a food. FDA states
that mere incidental presence of a substance (e.g., an extract) as an inherent
component of articles used for food does not establish that the substance
itself is “an article used for food.”
Therefore, if a dietary ingredient is not proven to be old
as discussed above, it is by law an NDI and cannot be lawfully marketed without
the required 75-day pre-market notice to FDA. For that reason FDA has issued a
regulation—“new dietary ingredient notification.”11 According to
this regulation, the following requirements are needed for an NDI submission to
FDA:
Name and address of manufacturer or distributor of the new dietary ingredient.
Name of the NDI.
Description of the NDI including a full characterization of the ingredient.
Level of NDI in dietary supplements which would include the amount included
in dosage form products and expected daily consumption.
Conditions of use recommended in product labeling which includes the labeled
suggested population for the ingredient (i.e., marketed to adults only or to all
age groups).
History of use of other evidence of safety establishing that when used at the
level of use and under the conditions of use the NDI will reasonably be expected
to be safe, including citations to published articles or other evidence that is
the basis for the manufacturer or distributor concluding that the new dietary
ingredient is safe.
Table 1. Summary of all New Dietary Ingredient (NDI) Submissions by
industry to FDA since passage of DSHEA in 1994 through June 2003
All NDI Submissions: 1994 (Oct) - 2003 (June)* |
238† |
% of Total |
Accepted
|
92 |
38% |
Rejected
|
141 |
59% |
Unknown‡
|
5 |
3% |
Reasons for Rejection |
Not reasonably expected to be safe |
96 |
Incomplete Filing/Lacking Data |
29 |
Does not meet definition of dietary supplement (ingredient is a food, drug
or medical device) |
12 |
Existence of IND§ before filing of NDI |
2 |
Not reasonably expected to be safe for children |
2 |
* FDA receipt dates vary considerably from the
date that NDI submissions are posted for public viewing. Theoretically, FDA must
post NDI filings in the public docket 90 days after receipt. The actual length
of time averages between 10–14 months.
† Determining the total number of NDIs filed with FDA requires some interpretation
of the filed reports. The authors of this paper found what they determined to
be 238 reports based on the data available from the FDA as of June 2003. FDA classifies
NDI submissions with a Report (“RPT”) number (except the first 2 submissions).
Some submissions received only one RPT number, but included multiple ingredients
that were evaluated individually by FDA. The authors classified each separate
evaluation as a unique submission. As of August 2004 there were 200 RPTs accessible
on the FDA website (www.fda.gov). The last RPT (# 200) was received by FDA on
June 30, 2003 and, based on the 90-day publication rule, was supposed to have
been posted on Sept 30, 2003. FDA did not post this notice until July 8, 2004.
Thus, for the purposes of this article, the “receipt” date is used
even though the NDI submissions aren’t posted until 10-14 months later.
In the 200 RPTs posted, treating ingredient evaluated by FDA as a unique filing,
the total becomes 238. Resubmissions are also considered unique NDI submissions
because they are evaluated as such by FDA. Therefore, when a new ingredient is
the subject of multiple NDI filings, each is considered a new entry as part of
the total.
‡ Five NDI submissions did not include a response by FDA.
§ IND = Investigative New Drug. |
The Acceptance/Rejection Rate of NDI Submissions
Based on NDI information obtained from the FDA website (www.fda.gov),
59% of the NDI notifications were rejected and not accepted for filing by FDA,
and 38% were accepted as of June 30, 2003. The rejection rate for botanicals was
higher (70%) than for non-botanical ingredients* (see Tables 1, 2, and 3). Various
reasons for not accepting the 75-day NDI submissions by FDA include the following:
Exposure studies done on the source of the ingredient were not conducted on
the actual ingredient.
Ingredient represented for a therapeutic indication. Therefore, the ingredient
is legally a drug that requires a new drug application filing and is not a dietary
supplement subject to DSHEA.
Ingredient is represented for use in the NDI submission as a conventional food
and therefore does not meet the legal definition of a dietary supplement.12
Data submitted in the NDI notification was for use of the ingredient for disease
conditions. FDA states that such studies have limited use for chronic long-term
use in a health population.
Clinical studies submitted utilized a non-oral dosage form; therefore, those
studies are not comparable for oral use of a dietary supplement.
Dietary ingredient submitted in the NDI notification met the legal definition
of a biological product according to FDA; therefore, it is not a dietary supplement.
NDI notification contained historical and foreign references wherein the ingredient
was studied for use in disease conditions but not for consumption and use as a
food.
Studies submitted show the pharmacological effects of the ingredient but were
not designed to study toxicity or safety of the ingredient for food use.
Description of the ingredient is insufficient to show specific qualitative
and quantitative characteristics of the ingredient. Studies submitted describe
an ingredient that is not proven to be the same ingredient subject to the 75-day
notification.
Submission does not discuss safety concerns that were mentioned in the clinical
studies submitted.
Reference to Chinese herbal medicine as a basis to show safety is not sufficient
to show a history of use that the ingredient is safe. These references show pharmacological,
clinical, or toxicological information on the source ingredient but there are
no studies on the ingredient per se or on the exact dose exposure submitted in
the 75-day NDI notice.
* Note: Although the rejection rate is higher for botanicals
than other ingredients, many NDI submissions were rejected on the grounds that
they were procedurally incomplete. The complexity of botanical filings for manufacturers
appears to be caused by multiple language documents, larger amount of historical
data, confusion about proper Latin nomenclature, and type of safety data required
by FDA. Given the lack of guidance from FDA on the NDI submission procedure, many
ingredients were therefore rejected simply on the grounds that they failed to
include certain components within the submissions.
FDA believes there will be minimal burden on the dietary supplement industry
to generate data to meet the requirements of the pre-market notification program.
FDA makes this assumption because they believe they are only requesting information
that the manufacturer or distributor should have already compiled and have on
file to qualify safety for a product. These data are required to support that
the ingredient or product marketed is “reasonably expected to be safe under the
conditions of use recommended or suggested in the labeling of the dietary supplement.”13
FDA believes the industry burden is approximately 20 hours of work per submission.
Many individuals, including the authors of this article, believe that this estimate
by FDA is unrealistic.
FDA also states that each NDI submission is applicable and
specific to the submitter. Other companies intending to market the same
ingredient would have to submit their own NDI submission. In other words, there
are no generic submissions that will benefit all other companies using the same
ingredient.14
Table 2. Summary of NDI submissions containing botanical ingredient
Botanical NDI Submissions: 1994 (Oct) - 2003 (June) |
113* |
% of Total |
Accepted
|
34 |
30% |
Rejected
|
79 |
70% |
Reasons for Rejection |
Not reasonably expected to be safe
|
62 |
Incomplete Filing/Lacking Data
|
13 |
Does not meet definition of dietary supplement (ingredient is a food, drug
or medical device)
|
4 |
* A complete listing of all 113 botanical NDI submissions and
their status is available online at www.herbalgram.org |
Table 3. Summary of all NDI submissions (botanical and non-botanical)
after FDA published the pre-market notification for NDI submission in September
of 1997. Until this date, FDA had not established criteria in which to evaluate
NDI submissions
NDI Submissions: 1997 (Sept) - 2003 (June) |
213 |
% of Total |
Accepted |
69 |
32% |
Rejected |
139 |
65% |
Unknown* |
5 |
3% |
* Five NDI submissions did not include a response by FDA. |
Among those who are aware of the legal requirements under DSHEA for filing
an NDI notification, some companies choose to ignore this component of DSHEA either
on the basis that there is no FDA enforcement or, if questioned, they are confident
that they could justify their position that the ingredient is “grandfathered.”
In the authors’ opinion, this gamble exposes a manufacturer to other legal problems.
The first is the potential product liability issue. If a manufacturer is selling
a product that is subject to a product liability lawsuit, it is possible that
the lawyer for the plaintiff will hire an expert (i.e., an attorney who specializes
in FDA matters) to review the products for compliance with DSHEA. If the expert
can take the position the product contained an NDI legally subject to the 75-day
NDI requirement, which was not submitted and accepted by FDA, the expert can argue
to a jury that the product was adulterated as a matter of law. This testimony
would be very persuasive in a product liability lawsuit.
Another liability involves the definition of a dietary
supplement. DSHEA amended the FDC Act in providing a legal definition of a
dietary supplement. This definition, as a matter of law, excludes a dietary
ingredient approved as a new drug under Section 505 of the FDC Act or an
article authorized for investigation as a new drug, antibiotic, or biological
for which substantial clinical investigations have been instituted and for
which the existence of such investigations has been made public, which was not
before such approval or authorization, marketed as a dietary supplement or as a
food.15 This definition is predicated on the ingredient’s being
lawfully marketed according to FDA. Thus, according to this definition, if a
marketed dietary ingredient is not proven to be old, and a pharmaceutical or
other company receives approval for an investigational new drug (IND, not to be
confused with NDI) for which the clinical studies were later published before the 75-day NDI notice was submitted, then the
dietary ingredient is disqualified as a dietary supplement under DSHEA and
further marketing is unlawful.
This is not a theoretical discussion. In the case of U.S. v.
Synthrax Innovations, Inc. the government discovered an investigational new
drug application had been in effect for tiratricol since 1990 (tiratricol, the
dietary supplement involved in this case, was an over-the-counter thyroid
preparation marketed as a metabolic accelerator and fat loss aid).16
The court held that this IND precluded tiratricol from being a dietary
supplement as a matter of law. The court found the facts demonstrated
substantial clinical investigations had been instituted for tiratricol, the
existence of such investigations had been made public, and tiratricol was not
marketed as a dietary supplement or a food prior to the authorization of the
IND. For those reasons the defendants in the case conceded that their product
could not be considered a dietary supplement. Additionally, FDA asserts the
legal position that it is not relevant in this determination whether the IND is
currently in force, just that it was filed and accepted by FDA at one time.
That is, the IND may be abandoned with no additional intention by the pharmaceutical
company to pursue drug status for the substance; yet because the IND was filed
prior to a dietary supplement company’s attempt to obtain NDI status for the
ingredient, dietary supplement status would not be allowed.
In comparing the safety requirements for foods to dietary
supplements it is clear there are different legal standards. For foods, an
added ingredient must be generally recognized as safe (GRAS) by qualified
experts. If not, the ingredient must be approved by FDA as a food additive before
it can be allowed on the market. In contrast for dietary supplements, a company
must have a basis for concluding that a supplement containing a “new dietary
ingredient” is reasonably expected to be safe under the condition of use
recommended or suggested in the product labeling. The new ingredient is legally
exempted from the requirement to be approved as a food additive (one of the
basic premises of DSHEA is that dietary supplements are not food additives).17 Additionally, the
company must notify FDA regarding the basis for concluding an NDI is safe for
its intended use at least 75 days before marketing.
If a company is
successful in obtaining an NDI for its product, there is no “seal of approval”
from FDA that can be included on the product label. If accepted, the agency
takes the position that because all research on the ingredient has not been
reviewed, FDA will make no statement regarding the ingredient’s safety. The
commonly misused statement “approved by the FDA” or other similar statements are
unacceptable based on this position. In contrast, a food additive, once
approved, is safe as a matter of law. A “successful” NDI submission establishes
FDC Act compliance but no FDA affirmation that the ingredient is safe for its
intended use.
Another notable difference in the legal requirements between
a food additive petition and an NDI submission is in the scientific validation
needed for the new food additive ingredient. A new food additive petition must
include full reports of investigations made with respect to safety of the food
additive, and those reports must include detailed data from animal and other
toxicology tests. In contrast, an NDI submission must include a history of use
of other evidence of safety that the ingredient will be reasonably expected to
be safe, including citations to published articles. While seemingly less
stringent for an NDI, it is in this area that FDA apparently is expecting more
studies and clinical information to show a reasonable basis for safety of a
dietary ingredient. This is not found in any published FDA guidance but is
discernable from the comments made by FDA for NDI submissions in which “no
reasonable basis of safety” was cited as the reason for rejection. It is an FDA
bias that results from the agency’s understanding of acceptable science for
other food ingredients found to be GRAS or subject to a food additive
regulation.
FDA regulations for marketing new dietary ingredients have
been present since the inception of DSHEA; however, they have not been actively
enforced. Some companies have used FDA’s tepid enforcement policy as a
rationale to rush new ingredients to market without sufficiently qualifying the
ingredient with a complete safety profile or determining its proper legal
status. Many responsible members of the herb and dietary supplement industry
are slowly integrating a more thorough investigative scientific approach for
new dietary ingredients, but the first-to-market mentality runs counter to this
practice. Requiring new ingredient suppliers, rather than marketers, to
establish whether the ingredient is “old” or “new” under FDA requirements would
be a step in the right direction. This could possibly limit the entry of
“unsubstantiated” ingredients into the market by forcing suppliers to qualify
the legal status of their ingredients; in other words, require those with the
best understanding of the science of an ingredient to qualify its safety. This
would remove a time-consuming task for those attempting to rush a new product
to market. Whatever the solution may be, it is advisable that all manufacturers
and marketers of dietary supplements thoroughly understand the legal
requirements for marketing new dietary ingredients before making a significant
investment in a new product.
Chris Noonan is President of HealthGuidance, a consulting firm located in
Santa Monica, CA, that specializes in new product development, marketing, and
copywriting for the natural products industry. Chris can be reached at chris@healthguidancela.com.
W. Patrick Noonan is an attorney who specializes in matters concerning products
regulated by the FDA with an office in Woodland Hills, CA, and he has a website
at www.wpnpc.com. Patrick can
be reached at pat@wpnpc.com.
References:
1. See Section 413(a) & (c) of the Food, Drug, and Cosmetic Act (FDC Act).
2. The
FDA requires that an old dietary ingredient be lawfully marketed. Warning
letter from FDA Director Joseph R. Baca, Office of Compliance, Center for Food
Safety and Applied Nutrition, directed to TwinLab, dated March 11, 2004
regarding the labeling and promotion of androstenedione as an ingredient.
3. Letter
from Felicia B. Satchell, Office of Nutritional Products, Labeling and Dietary
Supplements to Holly M. Bayne, Hyman, Phelps & McNamara, P.C., regarding
new dietary ingredient notification for Glucose Metabolism Modulator, July 15,
2001.
4. See
68 Fed. Reg. 51693, 51696 (August 28, 2003) where FDA states “In addition,
Herbs of Commerce, 2nd Edition (2000) does not represent an
authoritative compilation of botanical dietary ingredients that are marketed
before October 15, 1994 (i.e., botanicals that are new dietary ingredients)
under Section 413(c) of the Act.”
5. Foster
S. American Herbal Products Association’s Herbs of Commerce. Austin, TX: American Herbal Products Association,
1992.
6. Council
for Responsible Nutrition list of dietary ingredients “grandfathered” under
DSHEA. Washington, D.C.: Council for Responsible Nutrition. Sep., 1998.
7. U.S. Food and Drug Administration. New Dietary Ingredients in Dietary Supplements,
February 2001. Rpt 84, letter 4 (New Dietary Ingredient Submission for Glucose
Metabolism Modulator) available at <http://www.fda.gov/ohrms/dockets/dockets/95s0316/
rpt0084.pdf>
8. U.S. Food and Drug Administration Import Alert #45-06, Automatic detention
of Stevia leaves, extract of Stevia leaves, extract of Stevia leaves and food
containing Stevia. Revised Feb. 2, 1996, Attachment revised May 28, 2003. Available
at <http://www.fda.gov/ora/fiars/ora_import_ia4506.html>.
9. Pharmanex
Inc. v. Shalala, Case No. 2:97CV262K, CD. Utah, March 30, 2001.
10. “Chemical
alteration does not include a product that was subjected to minor loss of
volatile components, dehydration, lyophilization, milling, tincture or solution
in water, slurry, powder or solid in suspension.” See 140 Congressional Record
S 14801, Congressional “Statement of Agreement” on DSHEA (October 7, 1994)
point 5.
11. 21
CFR §190.6
12. See
§ 201(ff)(2)(B) of the FDC Act.
13. Premarket Notification for a New Dietary Ingredient 62 Fed. Reg. 49886,
49891 (September 23, 1997). Available at <http://www.cfsan.fda.gov/~lrd/fr97923e.html>.
14. U.S. Food and Drug Administration. New Dietary Ingredients in Dietary Supplements.
Available at <http://www.cfsan.fda.gov/~dms/ds-ingrd.html>.
61 Fed. Reg. 50774, 50777 (September 27, 1996).
15. See
§ 201(ff)(3)(B) of the FDA Act.
16. U.S.
v. Synthrax Innovat.on,149 F.Supp 2d 880 (2001).
17.See
§ 201(s)(6) of the FDC Act.
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