Page updated: 06/20/2006
This CPG supersedes section 440.100, Marketed New
Drugs Without Approved NDAs or ANDAs (CPG 7132c.02)
Sec. 440.100 Marketed New Drugs Without Approved NDAs or ANDAs (CPG 7132c.02)
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.
- Introduction
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.
- Background
- Reason for This Guidance
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.
- Historical Enforcement Approach
FDA estimates that, in the United States today, perhaps as many as several
thousand drug products are marketed illegally without required FDA approval.[2]
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.
- FDA's Enforcement Policy
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.
- Enforcement Priorities
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.
- Notice of Enforcement Action and Continued Marketing of Unapproved Drugs
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.[3] 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.[4] The only exception
to this policy is, as set forth elsewhere, that generally products subject
to an ongoing DESI[5]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[6]and any additional
period specifically provided in the proceeding (such as a delay in the effective
date of a final OTC drug monograph).[7] 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,[8]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.
- Special Circumstances — Newly Approved Product
Sometimes, a company may obtain approval of an NDA for a product that other
companies are marketing without approval.[9] 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;[10](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.[11]
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.[12]
- 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).
Appendix
BRIEF HISTORY OF FDA MARKETING APPROVAL REQUIREMENTS AND
CATEGORIES OF DRUGS THAT LACK REQUIRED FDA APPROVAL[13]
Key events in the history of FDA's drug approval regulation and the
categories of drugs affected by these events are described below.
- 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).
- 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.
- 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).[14]
- 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.
- 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 alsoLetter 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.
- 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).
- 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.
[1] This guidance has been prepared by the Center for Drug Evaluation
and Research (CDER) at the Food and Drug Administration.
[2] This rough estimate comprises several hundred drugs (different
active ingredients) in various strengths, combinations, and dosage forms from
multiple distributors and repackagers.
[3] For example, in 1997, FDA issued a Federal Register notice
declaring all orally administered levothyroxine sodium products to be new drugs
and requiring manufacturers to obtain approved new drug applications (62 FR
43535, August 14, 1997). Nevertheless, FDA gave manufacturers 3 years (later
extended to 4 (65 FR 24488, April 26, 2000)) to obtain approved applications
and allowed continued marketing without approved new drug applications because
FDA found that levothyroxine sodium products were medically necessary to treat
hypothyroidism and no alternative drug provided an adequate substitute.
[4] For example, FDA may take action at any time against a product
that was originally marketed before 1938, but that has been changed since 1938
in such a way as to lose its grandfather status (21 U.S.C. 321(p)).
[5] The Drug Efficacy Study Implementation (DESI) was the process
used by FDA to evaluate for effectiveness for their labeled indications over
3,400 products that were approved only for safety between 1938 and 1962. DESI
is explained more fully in the appendix to this document.
[6] 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.
[7] Sometimes, a final OTC drug monograph may have a delayed effective
date or provide for a specific period of time for marketed drugs to come into
compliance with the monograph. At the end of that period, drugs that are not
marketed in accordance with the monograph are subject to enforcement action
and the exercise of enforcement discretion in the same way as any other drug
discussed in this CPG.
[8] For purposes of this guidance, the terms grace period
and allow a grace period refer to an exercise of enforcement discretion
by the Agency (i.e., a period of time during which FDA, as a matter of
discretion, elects not to initiate a regulatory action on the ground that an
article is an unapproved new drug).
[9] These may be products that are the same as the approved product
or somewhat different, such as products of different strength.
[10] 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.
[11] Firms are reminded that this CPG does not create any right
to a grace period; the length of the grace period, if any, is solely at the
discretion of the Agency. For instance, firms should not expect any grace period
when the public health requires immediate removal of a product from the market,
or when the Agency has given specific prior notice in the Federal Register
or otherwise that a drug product requires FDA approval.
[12] The Agency understands that, under the Act, holders of NDAs
must list patents claiming the approved drug product and that newly approved
drug products may, in certain circumstances, be eligible for marketing exclusivity.
Listed patents and marketing exclusivity may delay the approval of competitor
products. If FDA believes that an NDA holder is manipulating these statutory
protections to inappropriately delay competition, the Agency will provide relevant
information on the matter to the Federal Trade Commission (FTC). In the past,
FDA has provided information to the FTC regarding patent infringement lawsuits
related to pending abbreviated new drug applications (ANDAs), citizen petitions,
and scientific challenges to the approval of competitor drug products.
[13] This brief history document should be viewed as a secondary
source. To determine the regulatory status of a particular drug or category
of drugs, the original source documents cited should be consulted.
[14] Products first marketed after a hearing notice is issued with
a different formulation than those covered by the notice are not considered
subject to the DESI proceeding. Rather, they need approval prior to marketing.
Under longstanding Agency policies, a firm holding an NDA on a product for which
a DESI hearing is pending must submit a supplement prior to reformulating that
product. The changed formulation may not be marketed as a related product under
the pending DESI proceeding; it is a new drug, and it must be approved for safety
and efficacy before it can be legally marketed. See, e.g., “Prescription
Drugs Offered for Relief of Symptoms of Cough, Cold, or Allergy” (DESI
6514), 49 FR 153 (January 3, 1984) (Dimetane and Actifed); “Certain Drugs
Containing Antibiotic, Corticosteroid, and Antifungal Components” (DESI
10826), 50 FR 15227 (April 17, 1985) (Mycolog). See also 21 U.S.C. 356a(c)(2)(A).
Similarly, firms without NDAs cannot market new formulations of a drug without
first getting approval of an NDA.