SUPPLEMENT ARTICLE

The US Food and Drug Administration

and Probiotics: Regulatory Categorization

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Frederick H. Degnan
King and Spalding, Washington, D.C.

Probiotics are living microorganisms that, when consumed, have the potential to confer a beneficial health
effect. Unfortunately for purveyors of probiotic products, the system of regulation delineated in the Food,
Drug, and Cosmetic Act is anything but “one size fits all.” How a probiotic product is used or is intended to
be used will govern the regulatory category or categories that the US Food and Drug Administration (FDA)
will assign to the product. The extent and nature of the restraints and data-collection requirements that may
be imposed on the marketing of a product hinge on how a product is categorized under the Act. More
specifically, the categorization of a product governs the respective regulatory burdens of an industry sponsor
and the FDA. Premarket systems, such as those for new drugs and biologics, place a heavy evidentiary burden
on the sponsor of a product. Postmarket systems, such as those for dietary supplements, place, at least initially,
a higher regulatory evidentiary burden on the FDA than on the product sponsor. This article explains regulatory
categorizations under the Food, Drug, and Cosmetic Act and their effects regarding the federal regulation of
probiotic products.

The Food, Drug, and Cosmetic (FDC) Act [1] lays out Accordingly, the notion of “categorization” is key to
a highly varied legal framework that governs a wide understanding the type and scope of regulation under
array of products. The system of regulation delineated the FDC Act and why the regulatory status of products
in the FDC Act is anything but “one size fits all.” When containing probiotics—components that are widely
one stands back and, employing a scientific and public viewed as safe and potentially beneficial—is far from
health perspective, thinks about how best to regulate cut-and-dried.
foods, drugs, biological products, medical devices, and Specifically, how a product is categorized under the
the array of other products that the US Food and Drug FDC Act governs the regulatory and evidentiary bur-
Administration (FDA) oversees, the diversity of re- dens that the sponsors and the FDA have with respect
quirements and sanctions found in the FDC Act makes to demonstration of the lawfulness of a given product.
sense. Simply put, some products, by virtue of the For example, if a product falls within the definition of
claims made on their behalf or of the risks they present, “food additive,” “new drug,” or “biological product,”
merit more concern, attention, substantiation, and vet- an evidentiary burden is placed on the sponsor to dem-
onstrate the propriety of its product before the product
ting than do others. Under the regulatory system laid
may be marketed lawfully. Conversely, other product
out in the FDC Act, the nature of the restraint that can
categorizations under the FDC Act result in regulation
be imposed on a given product (and on its purveyor)
under “postmarket” systems, which permit a manu-
hinges, in large part, on how the product is categorized.
facturer to place a product on the market without first
seeking clearance from the FDA. This, in turn, places
an evidentiary burden on the FDA to take action against
Reprints and correspondence: Frederick H. Degnan, King and Spalding, 1730
Pennsylvania Ave. NW, Ste. 1200, Washington, DC 20006-4795 (fdegnan
that product. Understandably, if the FDA has a regu-
@kslaw.com). latory concern about a marketed product, the FDA may
Clinical Infectious Diseases 2008; 46:S133–6 look for ways to categorize that product so that it is
 2008 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2008/4603S2-0019$15.00
subject to premarket, as opposed to postmarket, con-
DOI: 10.1086/523324 trols, which thereby reduces the regulatory and evi-

US Regulation of Probiotics • CID 2008:46 (Suppl 2) • S133

dentiary burden on the FDA with regard to restricting the “intended use” but rather simply by “use”; a “food” is circularly
marketing of that product. defined as “an article used for food” [6].
One final general point needs to be made about categori-
zation: regarding matters deemed by the FDA to present mean- REGULATORY CONSEQUENCES
ingful public health benefits, there has been, on occasion, a FOR PROBIOTICS THAT DEPEND
certain tension about how the FDA opts to administer and ON CATEGORIZATION
apply the FDC Act. This tension regards whether the FDA Drug, biological product, or new drug. The FDA’s current
should opt to foster restraint or to foster innovation. The FDA’s (and defensible) position is that a probiotic product intended
regulation of plant biotechnology provides a relatively recent for use as a “drug” is also a “biological product.” If the product

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and clear example of the agency’s conscious decision to choose meets the definition of “new drug” found in section 201(p) of
the latter. In doing so, the FDA considered the promising po- the FDC Act [7], the FDA will require an approved Biologics
tential of the technology to yield a safe and abundant food License Application for any intended clinical use and will apply
supply and, in light of that potential, opted to pursue regulatory the pertinent drug regulations, including the requirements of
pathways and categorizations that are tailored, in part, to en- an Investigational New Drug application for clinical inquiry
courage innovation, not restrict it. Of course, it must be kept into the safety and efficacy of the product.
in mind that, as a matter of routine, the FDA, as a public health The foregoing proposition raises the fundamental question,
protector, is naturally inclined to favor restraint in its efforts What is a new drug? “New drug” is a statutory term of art [8].
to ensure the public health. Nevertheless, history reveals that, A drug is a new drug if it is not “generally recognized as safe”
on occasion, the FDA is open to innovative regulatory ap- (GRAS) and not “generally recognized as effective” (GRAE) for
proaches when doing so is in the interest of public health. its intended use. GRAS and GRAE are demanding standards
Thus, in the context of probiotics, a scientific and policy- that call for expert agreement on whether publicly available
based issue arises: Do probiotics and the potential advantages data, of the same quantity and quality as required for the ap-
they offer in the context of potentially healthier and more- proval of a new drug application, exist and provide a basis for
beneficial consumer products provide a basis for the FDA to the conclusion that the drug is safe and effective for its intended
consider flexible regulatory pathways to encourage the devel- use.
opment of such products? If a probiotic falls within the definition of a “drug” and is
not GRAS and GRAE, then the probiotic also falls within the
PROBIOTICS: WHAT REGULATORY
definition of a “new drug” and, accordingly, is subject not only
CATEGORIES APPLY?
to rigid premarket clearance requirements but also to the testing
The use of probiotics in products can result in several regulatory requirements of the Investigational New Drug application, with
categories, 4 of which are fundamental: “food” or food ingre- regard to clinical studies. These requirements include the fol-
dient, “medical food,” “dietary supplement,” and “drug” or lowing steps:
“biological product.” The categorization of a product is deter-
mined in large part by its intended use, as in the following 1. Formal notification of the FDA about the intent to con-
examples. duct clinical studies
2. Submission to the FDA of comprehensive test protocols
1. An article is a medical food if it is intended for enteral 3. Development of an investigation plan
use in the “dietary management of a disease or condition for 4. Institutional review board oversight [9] (As a practical
which distinctive nutritional requirements have been estab- matter, whenever a company sponsors clinical research involv-
lished by medical evaluation” and is formulated to be admin- ing any product, regardless of the regulatory categorization[s]
istered “under the supervision of a physician” [2]. attending the product, it is sensible to take the necessary steps
2. An article is a dietary supplement if it is intended to to ensure that an institutional review board is used and that
“supplement the diet,” is or contains a “dietary ingredient,” is the fundamental commitment to the agency’s regulations [9]
“intended for ingestion,” and is not in “conventional” food are met.)
form [3].
3. An article is a drug if it is intended for the cure, miti- Dietary supplement. The regulatory consequences that ac-
gation, treatment, diagnosis, or prevention of disease [4]. company a probiotic product that is categorized as a dietary
4. An article is a biological product if it contains a virus, supplement differ dramatically from those that accompany a
serum, or toxin “applicable” to the prevention, treatment, or probiotic categorized as a drug. For example, if a probiotic
cure of a disease or condition [5]. product meets the definition of a dietary supplement, no pre-
market approval is required for the dietary ingredients; how-
Foods are the only FDA-regulated product categorized not by ever, notification requirements apply for “new dietary ingre-

S134 • CID 2008:46 (Suppl 2) • Degnan

dients” (i.e., dietary ingredients not marketed in the United be conditioned on appropriate medical supervision, and must
States before 15 October 1994) [10]. If a probiotic meets the address a distinctive nutritional need.
definition of a dietary supplement, the manufacturer may place In summary, as a practical matter, the intended use of a
the probiotic product on the market without premarket ap- probiotic product will determine its regulatory categorization
proval and may market the product with claims concerning the under the FDC Act. This categorization, in turn, will determine
effect that the product has on the structure or function of the the regulatory status of the product. For example, depending
body. The manufacturer, however, must notify the FDA of any on its intended use, a probiotic product can be categorized as
structure or function claim it is making for its dietary supple- a drug or biological product, as a dietary supplement, or as a
ment, and the manufacturer is expected to have, in hand, sub- food or food ingredient (including medical food). Depending

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stantiation for the claim, should the FDA challenge the pro- on which of these regulatory categories applies, a probiotic
priety of the claim. If a manufacturer of a dietary supplement product is subject to different requirements with respect to the
makes claims that fall within the statutory definition of a conduct of medical tests, premarket versus postmarket au-
“health claim” (i.e., claims that characterize a relationship be- thorization requirements, and evidentiary burdens to establish
tween a food [or a nutrient in the food] and a disease or health- safety and to substantiate claims.
related condition) [11], the manufacturer must secure either The spectrum of regulatory categorizations in the FDC Act
premarket clearance from the FDA for the claim or acquies- is by no means perfect. It does reflect, however, a deliberate
cence from the FDA that, as a matter of its enforcement dis- attempt on the part of Congress to avoid a one-size-fits-all
cretion, the agency will not take action against a “qualified” approach to the regulation of products. Because probiotics may
version of the claim. possess functional benefits beyond those that traditionally ac-
Food or food ingredient. If a probiotic is categorized as a company food ingredients, the categorization approach of the
food or food ingredient, the FDA will regulate the probiotic
FDC Act may appear arbitrary, if not problematic, when applied
component either as a food additive [12], subject to premarket
with full vigor (and rigor) to probiotic products. Nevertheless,
clearance, or simply as a GRAS food ingredient, subject to
the FDC Act reflects the understandable congressional judg-
regulation under the FDA’s postmarket controls that govern
ment that claims made on behalf of a product should be subject
the adulteration of food. As with “new drugs,” GRAS is a gate-
to a scale of increasingly demanding scientific scrutiny and
keeping concept. Similar to the concept in the context of new
substantiation requirements that depends, in large part, on the
drugs, a food ingredient can be GRAS only if there is no genuine
nature and context of the benefit claimed. This structure helps
dispute among qualified experts as to whether the available
create an environment that fosters scientific investigation. As
scientific information provides a basis for the conclusion that
scientific investigation of probiotics continues and as the safety
the probiotic component is safe for its intended use in food.
and benefits of probiotics become more clear, the varied nature
If a food ingredient is not GRAS, it is, by definition, a food
of the existing regulatory system may lead (as seen in the con-
additive and, as noted above, must go through a rigorous pre-
text of some products of biotechnology) to flexible agency pol-
market clearance process before it may be marketed lawfully
icies and practices that tend to encourage rational but inno-
[13]. To facilitate regulatory decision making for industry and
vative product categorizations designed to encourage the
the FDA alike, the agency has implemented a premarket “no-
development of beneficial probiotic products.
tification” process, whereby it will consider, on the request of
a sponsor, whether the question of GRAS status is presented
by the use of a food ingredient. If the FDA concludes that it Acknowledgments
has no questions about the GRAS status of such use, a man- Supplement sponsorship. This article was published as part of a sup-
ufacturer may proceed to market without further premarket plement entitled “Developing Probiotics as Foods and Drugs: Scientific and
considerations. A manufacturer or user of an ingredient is free Regulatory Challenges,” sponsored by the Drug Information Association,
the National Institutes of Health National Center for Complementary and
to make its own determination of whether an ingredient is
Alternative Medicine (1R13AT003805-01 to Patricia L. Hibberd), the Cal-
GRAS for a given use and, thus, is not subject to premarket ifornia Dairy Research Foundation, Chr. Hansen, the Dannon Company,
approval. The risk in this situation, of course, is that the FDA General Mills, Institut Rosell, and Yakult International.
might disagree with the manufacturer’s assessment and bring Potential conflicts of interest. F.H.D.: no conflicts.
enforcement action.
Medical food. If a probiotic product is categorized as a References
medical food, no premarket clearance requirements apply other
1. Federal Food, Drug, and Cosmetic Act. US Code title 21, sections 201
than food-additive and GRAS considerations with respect to et seq, 2007.
ingredients. Any claim made about a medical food must be 2. Federal Food, Drug, and Cosmetic Act. US Code title 21, section
limited to a focus on the dietary management of disease, must 360(ee), 2007.

US Regulation of Probiotics • CID 2008:46 (Suppl 2) • S135

3. Federal Food, Drug, and Cosmetic Act. US Code title 21, section 9. Food and drugs: institutional review boards. Code of Federal Regu-
321(ff), 2007. lations title 21, part 56, 2007.
4. Federal Food, Drug, and Cosmetic Act. US Code title 21, section 10. Federal Food, Drug, and Cosmetic Act. US Code title 21, section
321(g)(1)(B), 2007. 350b(c), 2007.
5. Federal Food, Drug, and Cosmetic Act. US Code title 21, section 262(a), 11. Federal Food, Drug, and Cosmetic Act. US Code title 21, section
2007. 343(r)(1)(B), 2007.
6. Federal Food, Drug, and Cosmetic Act. US Code title 21, section 321(f), 12. Federal Food, Drug, and Cosmetic Act. US Code title 21, section 321(s),
2007. 2007.
7. Federal Food, Drug, and Cosmetic Act. US Code title 21, section 13. Federal Food, Drug, and Cosmetic Act. US Code title 21, sections
201(p), 2007. 342(a)(2)(C)(i) and 349, 2007.
8. Federal Food, Drug, and Cosmetic Act. US Code title 21, section
321(p), 2007.

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S136 • CID 2008:46 (Suppl 2) • Degnan