U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
June 2006
Compliance
Guidance for FDA Staff and Industry
Marketed Unapproved Drugs —
Compliance Policy Guide
Sec. 440.100
Marketed New Drugs Without
Approved NDAs or ANDAs
Additional copies are
available from:
Office of Training and Communications
Division of Communications Management
Drug Information Branch, HFD-210
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane, Rockville, MD 20857
(Phone 301-827-4573)
Internet:
http://www.fda.gov/cder/guidance/index.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
June 2006
Compliance
Guidance for FDA Staff and Industry
Marketed Unapproved Drugs —
Compliance Policy Guide
Chapter - 4
Subchapter - 440
Sec.
440.100 Marketed New Drugs Without Approved NDAs or ANDAs
This
guidance represents the Food and Drug Administration's (FDA's)
current thinking on this topic. It does not create or confer
any rights for or on any person and does not operate to bind FDA
or the public. You can use an alternative approach if it
satisfies the requirements of the applicable statutes and
regulations. If you want to discuss an alternative approach,
contact the FDA staff responsible for implementing this
guidance. If you cannot identify the appropriate FDA staff,
call the appropriate number listed on the title page of this
guidance.
This compliance policy guide (CPG) describes
how we intend to exercise our enforcement discretion with regard
to drugs marketed in the United States that do not have required
FDA approval for marketing. This CPG supersedes section 440.100,
Marketed New Drugs Without Approved NDAs or ANDAs (CPG 7132c.02).
It applies to any drug required to have FDA approval for
marketing, including new drugs covered by the Over-the-Counter
(OTC) Drug Review, except for licensed biologics and veterinary
drugs.
FDA's guidance documents, including this
guidance, do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency's current thinking on a
topic and should be viewed only as recommendations, unless
specific regulatory or statutory requirements are cited. The use
of the word should in Agency guidances means that something
is suggested or recommended, but not required.
For historical reasons, some drugs are
available in the United States that lack required FDA approval for
marketing. A brief, informal summary description of the various
categories of these drugs and their regulatory status is provided
in Appendix A as general background for this document. The
manufacturers of these drugs have not received FDA approval to
legally market their drugs, nor are the drugs being marketed in
accordance with the OTC drug review. The new drug approval and
OTC drug monograph processes play an essential role in ensuring
that all drugs are both safe and effective for their intended
uses. Manufacturers of drugs that lack required approval,
including those that are not marketed in accordance with an OTC
drug monograph, have not provided FDA with evidence demonstrating
that their products are safe and effective, and so we have an
interest in taking steps to either encourage the manufacturers of
these products to obtain the required evidence and comply with the
approval provisions of the Federal Food, Drug, and Cosmetic Act
(the Act) or remove the products from the market. We want to
achieve these goals without adversely affecting public health,
imposing undue burdens on consumers, or unnecessarily disrupting
the market.
The goals of this guidance are to (1) clarify
for FDA personnel and the regulated industry how we intend to
exercise our enforcement discretion regarding unapproved drugs and
(2) emphasize that illegally marketed drugs must obtain FDA
approval.
FDA estimates that, in the United States
today, perhaps as many as several thousand drug products are
marketed illegally without required FDA approval.
Because we do not have complete data on illegally marketed
products, and because the universe of such products is constantly
changing as products enter and leave the market, we first have to
identify illegally marketed products before we can contemplate
enforcement action. Once an illegally marketed product is
identified, taking enforcement action against the product would
typically involve one or more of the following: requesting
voluntary compliance; providing notice of action in a Federal
Register notice; issuing an untitled letter; issuing a Warning
Letter; or initiating a seizure, injunction, or other proceeding.
Each of these actions is time-consuming and resource intensive.
Recognizing that we are unable to take action immediately against
all of these illegally marketed products and that we need to make
the best use of scarce Agency resources, we have had to prioritize
our enforcement efforts and exercise enforcement discretion with
regard to products that remain on the market.
In general, in recent years, FDA has employed
a risk-based enforcement approach with respect to marketed
unapproved drugs. This approach includes efforts to identify
illegally marketed drugs, prioritization of those drugs according
to potential public health concerns or other impacts on the public
health, and subsequent regulatory follow-up. Some of the specific
actions the Agency has taken have been precipitated by evidence of
safety or effectiveness problems that has either come to our
attention during inspections or been brought to our attention by
outside sources.
In the discussion that follows, we intend to
clarify our approach to prioritizing our enforcement actions and
exercising our enforcement discretion with regard to the universe
of unapproved, illegally marketed drug products in all
categories.
Consistent
with our risk-based approach to the regulation of pharmaceuticals,
FDA intends to continue its current policy of giving higher
priority to enforcement actions involving unapproved drug products
in the following categories:
Drugs with
potential safety risks. Removing potentially unsafe drugs
protects the public from direct and indirect health threats.
Drugs that
lack evidence of effectiveness. Removing ineffective
drugs protects the public from using these products in lieu of
effective treatments. Depending on the indication, some
ineffective products would, of course, pose safety risks as well.
Health fraud
drugs. FDA defines health fraud as "[t]he deceptive
promotion, advertisement, distribution or sale of articles . . .
that are represented as being effective to diagnose, prevent,
cure, treat, or mitigate disease (or other conditions), or provide
a beneficial effect on health, but which have not been
scientifically proven safe and effective for such purposes. Such
practices may be deliberate or done without adequate knowledge or
understanding of the article" (CPG Sec. 120.500). Of highest
priority in this area are drugs that present a direct risk to
health. Indirect health hazards exist if, as a result of reliance
on the product, the consumer is likely to delay or discontinue
appropriate medical treatment. Indirect health hazards will be
evaluated for enforcement action based on section
120.500, Health Fraud - Factors in Considering Regulatory Action
(CPG 7150.10). FDA's health fraud CPG outlines priorities for
evaluating regulatory actions against indirect health hazard
products, such as whether the therapeutic claims are significant,
whether there are any scientific data to support the safety and
effectiveness of the product, and the degree of vulnerability of
the prospective user group (CPG Sec. 120.500).
Drugs that
present direct challenges to the new drug approval and OTC drug
monograph systems. The drug approval and OTC drug
monograph systems are designed to avoid the risks associated with
potentially unsafe, ineffective, and fraudulent drugs. The drugs
described in the preceding three categories present direct
challenges to these systems, as do unapproved drugs that directly
compete with an approved drug, such as when a company obtains
approval of a new drug application (NDA) for a product that other
companies are marketing without approval (see section III.C.,
Special Circumstances – Newly Approved Product). Also included
are drugs marketed in violation of a final and effective OTC drug
monograph. Targeting drugs that challenge the drug approval or
OTC drug monograph systems buttresses the integrity of these
systems and makes it more likely that firms will comply with the
new drug approval and monograph requirements, which benefits the
public health.
Unapproved new
drugs that are also violative of the Act in other ways.
The Agency also intends, in circumstances that it considers
appropriate, to continue its policy of enforcing the preapproval
requirements of the Act against a drug or firm that also violates
another provision of the Act, even if there are other unapproved
versions of the drug made by other firms on the market. For
instance, if a firm that sells an unapproved new drug also
violates current good manufacturing practice (CGMP) regulations,
the Agency is not inclined to limit an enforcement action in that
instance to the CGMP violations. Rather, the Agency may initiate
a regulatory action that targets both the CGMP violation and
the violation of section 505 of the Act (21 U.S.C. 355). This
policy efficiently preserves scarce Agency resources by allowing
the Agency to pursue all applicable charges against a drug and/or
a firm and avoiding duplicative action. See United
States v. Sage Pharmaceuticals, Inc., 210 F.3d 475, 479-80 (5th
Cir. 2000).
Drugs that are reformulated to
evade an FDA enforcement action. The Agency is
also aware of instances in which companies that anticipate an FDA
enforcement action against a specific type or formulation of an
unapproved product have made formulation changes to evade that
action, but have not brought the product into compliance with the
law. Companies should be aware that the Agency is not inclined to
exercise its enforcement discretion with regard to such products.
Factors that the Agency may consider in determining whether to
bring action against the reformulated products include, but are
not limited to, the timing of the change, the addition of an
ingredient without adequate scientific justification (see, e.g.,
21 CFR 300.50 and 330.10(a)(4)(iv)), the creation of a new
combination that has not previously been marketed, and the claims
made for the new product.
FDA is not required to, and generally does
not intend to, give special notice that a drug product may be
subject to enforcement action, unless FDA determines that notice
is necessary or appropriate to protect the public health.
The issuance of this guidance is intended to provide notice
that any product that is being marketed illegally is subject to
FDA enforcement action at any time.
The only exception to this policy is, as set forth elsewhere, that
generally products subject to an ongoing DESI
proceeding or ongoing OTC drug monograph proceeding (i.e., an OTC
product that is part of the OTC drug review for which an effective
final monograph is not yet in place) may remain on the market
during the pendency of that proceeding
and any additional period specifically provided in the proceeding
(such as a delay in the effective date of a final OTC drug
monograph).
However, once the relevant DESI or OTC drug monograph proceeding
is completed and any additional grace period specifically provided
in the proceeding has expired, all products that are not in
compliance with the conditions for marketing determined in that
proceeding are subject to enforcement action at any time without
further notice (see, e.g., 21 CFR 310.6).
FDA intends to evaluate on a case-by-case
basis whether justification exists to exercise enforcement
discretion to allow continued marketing for some period of time
after FDA determines that a product is being marketed illegally.
In deciding whether to allow such a grace period,
we may consider the following factors: (1) the effects on the
public health of proceeding immediately to remove the illegal
products from the market (including whether the product is
medically necessary and, if so, the ability of legally marketed
products to meet the needs of patients taking the drug); (2) the
difficulty associated with conducting any required studies,
preparing and submitting applications, and obtaining approval of
an application; (3) the burden on affected parties of immediately
removing the products from the market; (4) the Agency's available
enforcement resources; and (5) any special circumstances relevant
to the particular case under consideration.
Sometimes, a company may obtain approval of
an NDA for a product that other companies are marketing without
approval.
We want to encourage this type of voluntary compliance with the
new drug requirements because it benefits the public health by
increasing the assurance that marketed drug products are safe and
effective — it also reduces the resources that FDA must expend on
enforcement. Thus, because they present a direct challenge to the
drug approval system, FDA is more likely to take enforcement
action against remaining unapproved drugs in this kind of
situation. However, we intend to take into account the
circumstances once the product is approved in determining how to
exercise our enforcement discretion with regard to the unapproved
products. In exercising enforcement discretion, we intend to
balance the need to provide incentives for voluntary compliance
against the implications of enforcement actions on the marketplace
and on consumers who are accustomed to using the marketed
products.
When a
company obtains approval to market a product that other companies
are marketing without approval, FDA normally intends to allow a
grace period of roughly 1 year from the date of approval of the
product before it will initiate enforcement action (e.g., seizure
or injunction) against marketed unapproved products of the same
type. However, the grace period provided is expected to vary from
this baseline based upon the following factors: (1) the effects
on the public health of proceeding immediately to remove the
illegal products from the market (including whether the product is
medically necessary and, if so, the ability of the holder of the
approved application to meet the needs of patients taking the
drug); (2) whether the effort to obtain approval was publicly
disclosed;
(3) the difficulty associated with conducting any required
studies, preparing and submitting applications, and obtaining
approval of an application; (4) the burden on affected parties of
removing the products from the market; (5) the Agency's available
enforcement resources; and (6) any other special circumstances
relevant to the particular case under consideration.
To
assist in an orderly transition to the approved product(s), in
implementing a grace period, FDA may identify interim dates by
which firms should first cease manufacturing unapproved
forms of the drug product, and later cease distributing the
unapproved product.
The length of any grace period and the nature
of any enforcement action taken by FDA will be decided on a
case-by-case basis. Companies should be aware that a Warning
Letter may not be sent before initiation of enforcement action and
should not expect any grace period that is granted to protect them
from the need to leave the market for some period of time while
obtaining approval. Companies marketing unapproved new drugs
should also recognize that, while FDA normally intends to allow a
grace period of roughly 1 year from the date of approval of an
unapproved product before it will initiate enforcement action
(e.g., seizure or injunction) against others who are marketing
that unapproved product, it is possible that a substantially
shorter grace period would be provided, depending on the
individual facts and circumstances.
The shorter the grace period, the more likely
it is that the first company to obtain an approval will have a
period of de facto market exclusivity before other products obtain
approval. For example, if FDA provides a 1-year grace period
before it takes action to remove unapproved competitors from the
market, and it takes 2 years for a second application to be
approved, the first approved product could have 1 year of market
exclusivity before the onset of competition. If FDA provides for
a shorter grace period, the period of effective exclusivity could
be longer. FDA hopes that this period of market exclusivity will
provide an incentive to firms to be the first to obtain approval
to market a previously unapproved drug.
D. Regulatory Action
Guidance
District offices are encouraged to refer to
CDER for review (with copies of labeling) any unapproved drugs
that appear to fall within the enforcement priorities in section
III.A. Charges that may be brought against unapproved drugs
include, but are not limited to, violations of 21 U.S.C. 355(a)
and 352(f)(1) of the Act. Other charges may also apply based on,
among others, violations of 21 U.S.C. 351(a)(2)(B) (CGMP), 352(a)
(misbranding), or 352(o) (failure to register or list).
BRIEF HISTORY OF FDA MARKETING APPROVAL REQUIREMENTS AND
CATEGORIES OF DRUGS THAT LACK REQUIRED FDA APPROVAL
Key events in the history of FDA's drug
approval regulation and the categories of drugs affected by these
events are described below.
A. 1938 and 1962 Legislation
The
original Federal Food and Drugs Act of June 30, 1906, first
brought drug regulation under federal law. That Act prohibited
the sale of adulterated or misbranded drugs, but did not require
that drugs be approved by FDA. In 1938, Congress passed the
Federal Food, Drug, and Cosmetic Act (the Act), which required
that new drugs be approved for safety. As discussed below, the
active ingredients of many drugs currently on the market were
first introduced, at least in some form, before 1938. Between
1938 and 1962, if a drug obtained approval, FDA considered drugs
that were identical, related, or similar (IRS) to the approved
drug to be covered by that approval, and allowed those IRS drugs
to be marketed without independent approval. Many manufacturers
also introduced drugs onto the market between 1938 and 1962 based
on their own conclusion that the products were generally
recognized as safe (GRAS) or based on an opinion from FDA that the
products were not new drugs. Between 1938 and 1962, the Agency
issued many such opinions, although all were formally revoked in
1968 (see 21 CFR 310.100).
B. DESI
In 1962,
Congress amended the Act to require that a new drug also be
proven effective, as well as safe, to obtain FDA approval. This
amendment also required FDA to conduct a retrospective evaluation
of the effectiveness of the drug products that FDA had approved as
safe between 1938 and 1962 through the new drug approval
process.
FDA contracted with the National Academy of
Science/National Research Council (NAS/NRC) to make an initial
evaluation of the effectiveness of over 3,400 products that were
approved only for safety between 1938 and 1962. The NAS/NRC
created 30 panels of 6 professionals each to conduct the review,
which was broken down into specific drug categories. The NAS/NRC
reports for these drug products were submitted to FDA in the late
1960s and early 1970s. The Agency reviewed and re-evaluated the
findings of each panel and published its findings in Federal
Register notices. FDA’s administrative implementation of the
NAS/NRC reports was called the Drug Efficacy Study Implementation
(DESI). DESI covered the 3,400 products specifically reviewed by
the NAS/NRCs as well as the even larger number of IRS products
that entered the market without FDA approval.
Because DESI products were covered by
approved (pre-1962) applications, the Agency concluded that, prior
to removing products not found effective from the market, it would
follow procedures in the Act and regulations that apply when an
approved new drug application is withdrawn:
·
All initial DESI determinations are published in the
Federal Register and, if the drug is found to be less than
fully effective, there is an opportunity for a hearing.
·
The Agency considers the basis of any hearing
request and either grants the hearing or denies the hearing on
summary judgment and publishes its final determination in the
Federal Register.
·
If FDA's final determination classifies the drug as
effective for its labeled indications, as required by the Act, FDA
still requires approved applications for continued marketing of
the drug and all drugs IRS to it – NDA supplements for those drugs
with NDAs approved for safety, or new ANDAs or NDAs, as
appropriate, for IRS drugs. DESI-effective drugs that do not
obtain approval of the required supplement, ANDA, or NDA are
subject to enforcement action.
·
If FDA's final determination classifies the drug as
ineffective, the drug and those IRS to it can no longer be
marketed and are subject to enforcement action.
1. Products
Subject to Ongoing DESI Proceedings
Some unapproved marketed products are
undergoing DESI reviews in which a final determination regarding
efficacy has not yet been made. In addition to the products
specifically reviewed by the NAS/NRC (i.e., those products
approved for safety only between 1938 and 1962), this group
includes unapproved products identical, related, or similar to
those products specifically reviewed (see 21 CFR 310.6).
In virtually all these proceedings, FDA has made an initial
determination that the products lack substantial evidence of
effectiveness, and the manufacturers have requested a hearing on
that finding. It is the Agency's longstanding policy that
products subject to an ongoing DESI proceeding may remain on the
market during the pendency of the proceeding. See, e.g.,
Upjohn Co. v. Finch, 303 F. Supp. 241, 256-61 (W.D. Mich.
1969).
2. Products
Subject to Completed DESI Proceedings
Some unapproved marketed products are subject
to already-completed DESI proceedings and lack required approved
applications. This includes a number of products IRS to DESI
products for which approval was withdrawn due to a lack of
substantial evidence of effectiveness. This group also includes a
number of products IRS to those DESI products for which FDA made a
final determination that the product is effective, but
applications for the IRS products have not been both submitted and
approved as required under the statute and longstanding
enforcement policy (see 21 CFR 310.6). FDA considers all
products described in this paragraph to be marketed illegally.
C.
Prescription Drug Wrap-Up
As mentioned
above, many drugs came onto the market before 1962 without FDA
approvals. Of these, many claimed to have been marketed prior to
1938 or to be IRS to such a drug. Drugs that did not have
pre-1962 approvals and were not IRS to drugs with pre-1962
approvals were not subject to DESI. For a period of time,
FDA did not take action against these drugs and did not take
action against new unapproved drugs that were IRS to these
pre-1962 drugs that entered the market without approval.
Beginning in 1983, it was discovered that one
drug that was IRS to a pre-1962 drug, a high potency Vitamin E
intravenous injection named E-Ferol, was associated with adverse
reactions in about 100 premature infants, 40 of whom died.
In November of 1984, in response to this, a congressional
oversight committee issued a report to FDA expressing the
committee's concern regarding the thousands of unapproved drug
products in the marketplace.
In response to the E-Ferol tragedy, CDER
assessed the number of pre-1962 non-DESI marketed drug products.
To address those drug products, the Agency significantly revised
and expanded CPG section 440.100 to cover all marketed unapproved
prescription drugs, not just DESI products. The program
for addressing these marketed unapproved drugs and certain others
like them became known as the Prescription Drug Wrap-Up.
Most of the Prescription Drug Wrap-Up drugs first entered the
market before 1938, at least in some form. For the most part, the
Agency had evaluated neither the safety nor the effectiveness of
the drugs in the Prescription Drug Wrap-Up.
A drug that was subject to the Prescription
Drug Wrap-Up is marketed illegally, unless the manufacturer of
such a drug can establish that its drug is grandfathered or
otherwise not a new drug.
Under the 1938 grandfather
clause (see 21 U.S.C. 321(p)(1)), a drug product that was
on the market prior to passage of the 1938 Act and which contained
in its labeling the same representations concerning the conditions
of use as it did prior to passage of that Act was not considered a
new drug and therefore was exempt from the requirement of
having an approved new drug application.
Under the 1962 grandfather
clause, the Act exempts a drug from the effectiveness requirements
if its composition and labeling has not changed since 1962 and if,
on the day before the 1962 Amendments became effective, it was (a)
used or sold commercially in the United States, (b) not a new drug
as defined by the Act at that time, and (c) not covered by an
effective application. See Pub. L. 87-781, section 107
(reprinted following 21 U.S.C.A. 321); see also USV
Pharmaceutical Corp. v. Weinberger, 412 U.S. 655, 662-66
(1973).
The two
grandfather clauses in the Act have been construed very narrowly
by the courts. FDA believes that there are very few drugs
on the market that are actually entitled to grandfather status
because the drugs currently on the market likely differ from the
previous versions in some respect, such as formulation, dosage or
strength, dosage form, route of administration, indications, or
intended patient population. If a firm claims that its product is
grandfathered, it is that firm's burden to prove that assertion.
See 21 CFR 314.200(e)(5); see also United States
v. An Article of Drug (Bentex Ulcerine), 469 F.2d 875, 878
(5th Cir. 1972); United States v. Articles of Drug Consisting
of the Following: 5,906 Boxes, 745 F.2d 105, 113 (1st
Cir 1984).
Finally, a product would not be considered a
new drug if it is generally recognized as safe and
effective (GRAS/GRAE) and has been used to a material extent and
for a material time. See
21 U.S.C. 321(p)(1) and (2).
As with the grandfather clauses, this has been construed very
narrowly by the courts. See, e.g., Weinberger v. Hynson,
Westcott & Dunning, Inc., 412 U.S. 609 (1973);
United States v. 50 Boxes More or Less Etc., 909 F.2d 24,
27-28 (1st Cir. 1990); United States v. 225 Cartons . . .
Fiorinal, 871 F.2d 409 (3rd Cir. 1989).
See also
Letter from Dennis E. Baker, Associate Commissioner for Regulatory
Affairs, FDA, to Gary D. Dolch, Melvin Spigelman, and Jeffrey A.
Staffa, Knoll Pharmaceutical Co. (April 26, 2001) (on file in FDA
Docket No. 97N-0314/CP2) (finding that Synthroid, a levothyroxine
sodium product, was not GRAS/GRAE).
As mentioned above, the Agency
believes it is not likely that any currently marketed prescription
drug product is grandfathered or is otherwise not a new drug.
However, the Agency recognizes that it is at least theoretically
possible. No part of this guidance, including the Appendix, is a
finding as to the legal status of any particular drug product. In
light of the strict standards governing exceptions to the approval
process, it would be prudent for firms marketing unapproved
products to carefully assess whether their products meet these
standards.
D.
New Unapproved Drugs
Some
unapproved drugs were first marketed (or changed) after 1962.
These drugs are on the market illegally. Some also may have
already been the subject of a formal Agency finding that they are
new drugs. See, e.g., 21 CFR 310.502 (discussing, among
other things, controlled/timed release dosage forms).
E. Over-the-Counter (OTC) Drug
Review
Although OTC drugs were originally included
in DESI, FDA eventually concluded that this was not an efficient
use of resources. The Agency also was faced with resource
challenges because it was receiving many applications for
different OTC drugs for the same indications. Therefore, in 1972,
the Agency implemented a process of reviewing OTC drugs through
rulemaking by therapeutic classes (e.g., antacids,
antiperspirants, cold remedies). This process involves convening
an advisory panel for each therapeutic class to review data
relating to claims and active ingredients. These panel reports
are then published in the Federal Register, and after FDA
review, tentative final monographs for the classes of drugs are
published. The final step is the publication of a final monograph
for each class, which sets forth the allowable claims, labeling,
and active ingredients for OTC drugs in each class (see, e.g.,
21 CFR part 333). Drugs marketed in accordance with a final
monograph are considered to be generally recognized as safe and
effective (GRAS/GRAE) and do not require FDA approval of a
marketing application.
Final monographs have been published for the
majority of OTC drugs. Tentative final monographs are in place for
virtually all categories of OTC drugs. FDA has also finalized a
number of negative monographs that list therapeutic
categories (e.g., OTC daytime sedatives, 21 CFR 310.519) in
which no OTC drugs can be marketed without approval. Finally, the
Agency has promulgated a list of active ingredients that cannot be
used in OTC drugs without approved applications because there are
inadequate data to establish that they are GRAS/GRAE (e.g.,
phenolphthalein in stimulant
laxative products, 21 CFR 310.545(a)(12)(iv)(B)).
OTC drugs covered by ongoing OTC drug
monograph proceedings may remain on the market as provided in
current enforcement policies (see, e.g., CPG sections
450.200 and 450.300, and 21 CFR part 330). This document does not
affect the current enforcement policies for such drugs.
OTC drugs that need approval, either because their ingredients or
claims are not within the scope of the OTC drug review or because
they are not allowed under a final monograph or another final
rule, are illegally marketed. For example, this group would
include a product containing an ingredient determined to be
ineffective for a particular indication or one that exceeds the
dosage limit established in the monograph. Such products are new
drugs that must be approved by FDA to be legally marketed.
For example, at the Agency’s discretion, we may provide for a
shorter grace period if an applicant seeking approval of a
product that other companies are marketing without approval
agrees to publication, around the time it submits the approval
application, of a Federal Register notice informing the public
that the applicant has submitted that application. A
shortened grace period may also be warranted if the fact of
the application is widely known publicly because of applicant
press releases or other public statements. Such a grace
period may run from the time of approval or from the time the
applicant has made the public aware of the submission, as the
Agency deems appropriate.