CPG Sec. 440.100 Marketed New Drugs Without Approved NDAs and ANDAs  
Guidance for FDA Staff and Industry1  
Marketed Unapproved Drugs   
Compliance Policy Guide 
Chapter 4 
Subchapter 440 
This guidance represents the Food and Drug Administrations (FDAs) 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 the approach 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. 
I. 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 is a revision of a guidance of the same name that was issued in June 2006. The guidance 
has been revised to state that the enforcement priorities and potential exercise of enforcement 
discretion discussed in the guidance apply only to unapproved new drugs (including new drugs covered 
by the Over-the-Counter (OTC) Drug Review), except for licensed biologics and veterinary drugs, that are 
commercially used or sold2 prior to September 19, 2011. 
FDAs guidance documents, including this guidance, do not establish legally enforceable responsibilities. 
Instead, guidances describe the Agencys 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. 
II. BACKGROUND 
A. 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 FD&C 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. 
B. 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.3 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. 
III. FDAS 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 unapproved, illegally marketed drug products. 
The enforcement priorities and potential exercise of enforcement discretion discussed in this guidance 
apply only to unapproved drug products that are being commercially used or sold as of September 19, 
2011. All unapproved drugs introduced onto the market after that date are subject to immediate 
enforcement action at any time, without prior notice and without regard to the enforcement priorities 
set forth below. In light of the notice provided by this guidance, we believe it is inappropriate to exercise 
enforcement discretion with respect to unapproved drugs that a company (including a manufacturer or 
distributor) begins marketing after September 19, 2011.  For unapproved drugs commercially used or sold as of September 19, 2011, FDAs enforcement 
priorities are described below. 
A. 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 Sec. 120.500). 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 FD&C Act against a drug or firm that also violates another provision of the FD&C  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 FD&C 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, for example, 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. 
B. 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.4 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.5 The only 
exception to this policy is, as set forth elsewhere, that generally products subject to an ongoing DESI6 
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 proceeding7 and any additional period specifically provided in the proceeding (such 
as a delay in the effective date of a final OTC drug monograph).8 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, for example, 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,9 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. However, as stated above, FDA does not intend to apply any 
such grace period to an unapproved drug that was introduced onto the market after September 19, 
2011. 
C. Special Circumstances  Newly Approved Product 
Sometimes, a company may obtain approval of an NDA for a product that other companies are 
marketing without approval.10 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;11 (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.12 
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.13 
D. Regulatory Action Guidance 
ORA staff 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 
FD&C 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 APPROVAL14 
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 FD&C 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. FDAs 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 FD&C 
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 FD&C 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).15 
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 FD&C 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 FD&C Act at that time, and (c) not covered by an effective application. See Public 
Law 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 FD&C 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. 
1 This guidance has been prepared by the Center for Drug Evaluation and Research (CDER) at the Food 
and Drug Administration. 
2 For the purposes of this guidance, the term commercially used or sold means that the product has 
been used in a business or activity involving retail or wholesale marketing and/or sale. 
3 This rough estimate comprises several hundred drugs (different active ingredients) in various 
strengths, combinations, and dosage forms from multiple distributors and repackagers. 
4 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.   5 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)). 
6 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. 
7 OTC drugs covered by ongoing OTC drug monograph proceedings may remain on the market as 
provided in current enforcement policies. See, for example, CPG sections 450.200 and 450.300 and 21 
CFR part 330. This document does not affect the current enforcement policies for such drugs. 
8 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. 
9 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). 
10 These may be products that are the same as the approved product or somewhat different, such as 
products of different strength. 
11 For example, at the Agencys 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. 
12 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. 
13 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. 
14 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. 
15 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.