by Suzan Onel
T
here may be a significantly less expensive means
for dietary supplement and cosmetic manufacturers to make therapeutic claims than the traditional new drug approval (NDA) application process. The
U.S. Food and Drug Administration (FDA) recently issued a
final regulation that expands the criteria and procedures for
over-the-counter (OTC) conditions to be included in the OTC
drug monograph system.1
Under the new regulation, which became effective
February 22, 2002, FDA will now consider foreign marketing experience in assessing the inclusion of an OTC condition in the OTC drug monograph system. An “OTC condition” is defined as an active ingredient or botanical drug
substance (including combinations of active ingredients or
botanical drug substances), dosage form, dosage strength, or
route of administration marketed for a specific OTC use.2 To
be eligible for consideration under this regulation, the OTC
condition must have been marketed for OTC purchase
outside the U.S. (irrespective of whether as a drug, cosmetic,
or dietary supplement) for a “material time” and to a
“material extent.”
The expansion of the OTC drug provisions to include
foreign marketing data represents a fundamental change for
the agency. Historically, FDA has interpreted the “use”
provision in the Federal Food, Drug, and Cosmetic Act’s
(FDCA’s) “new drug” definition to mean use in the United
States only. The material time/extent regulation expands the
existing criteria and procedures for classifying OTC drugs as
generally recognized as safe and effective (GRAS/E) to
include OTC conditions that have been used for a material
time and to a material extent outside the United States. FDA
first issued an advance notice of proposed rulemaking on this
subject in 1996.3 The advance notice was followed in 1999
by a proposed regulation,4 which was finalized, with some
changes, with the 2002 final rule.
The material time/extent regulation establishes a two-step
process by which FDA first reviews a time and extent
application (TEA) and, after the condition is found eligible
Ms. Onel is a Partner in the law office
of Kirkpatrick & Lockhart, L.L.P.,
Washington, D.C.
24
UPDATE
September/October 2002
based on the TEA, FDA would evaluate the condition for
general recognition of safety and effectiveness. If, based on
the TEA, an OTC condition is found eligible, the FDA would
publish a notice of eligibility in the Federal Register and
place the TEA on public display. The sponsor and other
interested parties would then submit safety and effectiveness
data that FDA would review in accordance with FDA’s OTC
drug monograph requirements. If the OTC condition is not
found eligible, the TEA would not become publicly available, but a letter from the agency to the sponsor stating the
reasons for the decision would be made publicly available.
According to the final rule, the following information
must be included in a TEA submission: a detailed chemical
description, how and where a condition has been marketed, a
cumulative total of dosage units, and adverse event information. A minimum of five continuous years of marketing
experience in one country is required and, as part of the
subsequent safety and effectiveness review, an official or
proposed United States Pharmacopoeia-National Formulary
(USP-NF) drug monograph must be submitted.
While the final rule does not establish concrete timelines,
FDA stated that it would “strive to complete TEA evaluations
within 90 to 180 days of receipt.”5 The agency also stated
that it would give priority review to citizen petitions converted to TEAs and submitted within 120 days of the rule’s
publication.
Consistent with FDA’s current OTC drug policy, FDA
will allow interim marketing of new OTC conditions under
certain circumstances. Active ingredients or botanicals that
are reviewed under a TEA for use in a nonfinal or pending
OTC monograph (e.g., proposed or tentative final rule
status), will be eligible for interim marketing if they are
recognized in an official USP-NF drug monograph that sets
forth the standards of identity, strength, quality, and purity.
For those conditions proposed to be included in a final OTC
drug monograph or in situations where an OTC drug
monograph or official USP-NF monograph does not exist,
interim marketing will not be allowed.
So, what conditions are likely candidates for the TEA
process? Ingredients marketed in Europe as cosmetics (e.g.,
sunscreens, antiperspirants, antidandruff shampoos, and skin
protectants, to name a few) present likely prospects for
inclusion in the OTC drug monograph system through the
material time/extent regulatory process. Botanical ingredi-
w w w. f d l i . o r g
ents also are promising prospects because they generally lack
patent protection and, therefore, do not provide the same
financial incentives to pursue an NDA application, as do
other active ingredients. As a result, the material time/extent
regulation appears to provide a more economic alternative
for these ingredients to carry therapeutic claims that go
beyond those allowed under the dietary supplement regulatory regime. It also offers the OTC drug industry a means for
expanding existing OTC monograph conditions.
Before a company decides to pursue the TEA approach to
OTC drug marketing, however, it should carefully consider
the potential benefit from inclusion in the OTC drug monograph system. In certain circumstances, it may be equally, if
not more, beneficial for a product to remain characterized as
a dietary supplement. FDA stated in the preamble to its final
rule on dietary supplement structure/function claims that
OTC drug claims that refer to a nonspecific group of
conditions that have a variety of causes (e.g., gas, occasional
heartburn, weight gain, fatigue, or drowsiness) may be
acceptable structure/function claims.6 Thus, depending on
the situation, a company already may be able to make the
desired OTC drug monograph claims as a supplement
product, with the added benefit of not having to follow drug
good manufacturing practices (GMPs).
A company also may choose to continue marketing its
botanical product as a dietary supplement because of a
negative monograph issued by FDA specifically prohibiting
certain claims. Examples of this are aphrodisiac and daytime
sedative claims.7 Because the Dietary Supplement Health
and Education Act (DSHEA) applies a different standard,
dietary supplements can make aphrodisiac claims such as
“arouses or increases sexual desire” and “improves sexual
performance” and sedative claims such as “helps you relax”
and “gently soothes away tension.” Thus, in certain circumstances, the OTC drug monograph system does not offer
botanical ingredients the opportunity for expanded claims.
Finally, some botanicals’ mechanism of action may not fit
cleanly within the terms of an existing OTC drug monograph. For example, echinacea is touted for its affect on the
immune system; however, such claims do not translate easily
into the framework of the existing OTC drug cough/cold
monograph, which focuses on specific system effects such as
antitussive and nasal decongestant.
Nevertheless, the material time/extent application process
offers exciting possibilities for botanical ingredients that
have historical marketing data. For example, ginger, valerian,
and milk thistle—currently marketed as dietary supplements
with indications relating to healthy digestive function,
supporting a restful sleep, and healthy bowel function,
respectively—may be good candidates for the antiemetic,
FDLI
nighttime sleep-aid, and laxative OTC drug monographs,
respectively. All three ingredients have substantial foreign
use histories, USP-NF monographs, and traditional uses that
are consistent with the terms of the above-mentioned OTC
drug monographs. Manufacturers of other botanicals with
therapeutic effects, such as fever reduction, anti-inflammation, nasal decongestion, and pain relief, may find the
material time/extent OTC drug application process a valuable
means for making claims currently not allowed under the
dietary supplement regime and too expensive to pursue under
an NDA.
Ingredients used in combination dietary supplement/OTC
drug products also may present promising candidates for the
material time/extent regulatory process. FDA has been
increasingly vocal about such combinations, indicating
through recent warning letters and public statements that
simply placing dual labels that identify supplement and drug
uses may not be sufficient.8 FDA has asserted that when an
ingredient is added to an OTC drug, the resulting combination is a new drug, even if the ingredient can be separately
regulated as a supplement. As a result, the final product
would require the submission of an NDA application because
the combination has not been reviewed under the OTC drug
review process. The material time/extent application process
may offer an alternative for those combination products that
contain ingredients that fit within an existing monograph
category, have an official USP-NF monograph, and have
sufficient foreign marketing data.
In sum, the material time/extent regulation offers a
promising alternative to the NDA process. Cosmetic,
botanical, and combination supplement/OTC drug products
manufacturers may want to consider this option, alone or as
part of an industry coalition, when the OTC drug system
offers expanded labeling opportunities and significant
foreign use data exists.
1
67 Fed. Reg. 3060, 3074 (Jan. 23, 2002) (to be codified at 21 C.F.R. pt. 330).
2
21 C.F.R. § 330.14(a).
3
61 Fed. Reg. 51,625 (Oct. 3, 1996).
4
64 Fed. Reg. 71,062 (Dec. 20, 1999).
5
67 Fed. Reg. at 3065.
6
See generally 65 Fed. Reg. 1000, 1031 (Jan. 6, 2000).
7
21 C.F.R. §§ 310.528, 310.519.
8
See e.g., FDA Warning Letter to B.F. Ascher & Company, Inc. (Oct. 16, 2001) and
FDA Warning Letter to Omni Nutraceuticals, Inc. (Oct. 16, 2001).
September/October 2002
UPDATE
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