[Federal Register Volume 86, Number 101 (Thursday, May 27, 2021)]
[Notices]
[Pages 28605-28608]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2021-11257]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2020-Z-2200]


Termination of the Food and Drug Administration's Unapproved 
Drugs Initiative; Request for Information Regarding Drugs Potentially 
Generally Recognized as Safe and Effective; Withdrawal

AGENCY: Food and Drug Administration (FDA), Department of Health and 
Human Services (HHS).

ACTION: Notice; withdrawal.

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SUMMARY: The Department of Health and Human Services (HHS or the 
Department) is issuing this document to withdraw a legally and 
factually inaccurate notice and request for information published in 
the Federal Register on November 25, 2020, entitled ``Termination of 
the Food and Drug Administration's Unapproved Drugs Initiative; Request 
for Information Regarding Drugs Potentially Generally Recognized as 
Safe and Effective.'' This notice also ends the period for submission 
of responses to Part II of the November 25, 2020, notice and request 
for information.

DATES: The notice and the request for information are withdrawn as of 
May 27, 2021.

FOR FURTHER INFORMATION CONTACT: Anuj Shah, Center for Drug Evaluation 
and Research, Food and Drug Administration, 10903 New Hampshire Ave., 
Bldg. 51, Rm. 6224, Silver Spring, MD 20993, 301-796-2246.

SUPPLEMENTARY INFORMATION: On November 25, 2020, HHS published a notice 
and a request for information in the Federal Register entitled 
``Termination of the Food and Drug Administration's Unapproved Drugs 
Initiative; Request for Information Regarding Drugs Potentially 
Generally Recognized as Safe and Effective'' (the HHS Notice) (85 FR 
75331). The HHS Notice stated that it was ``terminating'' the FDA's 
Unapproved Drugs Initiative (UDI) effective 30 days from publication of 
the HHS Notice in the Federal Register, by withdrawing FDA's ``Marketed 
Unapproved Drugs Compliance Policy Guide'' (CPG

[[Page 28606]]

440.100). The HHS Notice also requested public input on four topics 
that relate to the statutory exemptions from the definition of ``new 
drug'' in the Federal Food, Drug, and Cosmetic Act (FD&C Act). The 
request for responses stated that: ``The Department will consider 
information submitted by the public in response to Part II of this 
Notice on a rolling basis, and until further notice.'' The responses 
were directed to be submitted to an HHS email address with a specific 
subject line.
    Because the HHS Notice contained multiple legal and factual 
inaccuracies, it is hereby withdrawn. Further, no responses or 
information submitted to the HHS email Import@hhs.gov, in response to 
the HHS Notice and request for information, on or after May 27, 2021 
will be considered by HHS or FDA. All website statements and other 
informal issuances with respect to the HHS Notice are also hereby 
withdrawn. The HHS Notice withdrew FDA's guidance CPG 440.100, but that 
withdrawal does not represent a change in the legal obligations that 
apply to new drugs or to FDA's existing enforcement authority over 
unapproved new drugs.
    Central to the legal and factual inaccuracies in the HHS Notice is 
its misinterpretation of the term ``new drug.'' The definition of 
``drug'' in section 201(g)(1) of the FD&C Act (21 U.S.C. 321(g)(1)) 
includes articles intended for use in the ``diagnosis, cure, 
mitigation, treatment, or prevention of disease in man or other 
animals''; ``articles (other than food) intended to affect the 
structure or any function of the body of man or other animals''; and 
articles ``intended for use as a component'' of the foregoing articles. 
A drug is a ``new drug,'' and is generally subject to the requirements 
for ``new drugs,'' unless the drug is generally recognized by qualified 
experts as safe and effective (GRASE) for its labeled uses and used to 
a material extent or for a material time or the drug is grandfathered 
because it was marketed before 1938 (section 201(p) of the FD&C Act). A 
separate ``grandfather'' clause exempts a drug from the 
``effectiveness'' requirements if, before 1962, the drug was: (1) Used 
or sold commercially in the United States; (2) not a ``new drug'' as 
defined by the FD&C Act at that time; and (3) not covered by an 
effective application. Under section 505(a) of the FD&C Act (21 U.S.C. 
355(a)), before any ``new drug'' may be legally marketed in the United 
States, it must be the subject of an approved application submitted 
pursuant to section 505(b) or section 505(j) of the FD&C Act, unless an 
exception applies. A biological product (defined in section 351(i) of 
the Public Health Service Act (PHS Act) (42 U.S.C. 262(i)) with an 
approved license under section 351 of the PHS Act is not required to 
have an approved application under section 505 of the FD&C Act.
    For decades, FDA has interpreted the word ``drug'' in the term 
``new drug'' to refer to the entire drug product and not just its 
active ingredient. This interpretation has significant implications for 
public health. An active ingredient can have different effects on the 
body depending on the formulation of the drug and its route of 
administration (e.g., topical vs. intravenous), among other things.\1\ 
That is why when it reviews an application, FDA carefully evaluates, 
for each drug product, not only the active ingredient but also 
information about the drug's formulation, route of administration, 
labeling, inactive ingredients, bioavailability, and manufacturing 
processes. In accordance with this approach, FDA has consistently 
argued in the courts that the term ``drug'' in ``new drug'' means the 
entire drug product and not only an active ingredient, and courts, 
including the U.S. Supreme Court, have agreed with FDA's 
interpretation. See U.S. v. Generix Drug Corp., 460 U.S. 453, 458-59 
(1983) (the FD&C Act's definition of ``new drug'' applies to the entire 
drug product rather than the active ingredient); see also U.S. v. Premo 
Pharmaceutical Lab., 629 F.2d 785 (2d Cir. 1980). FDA regulations 
incorporate FDA's interpretation of ``new drug'' (see 21 CFR 314.200), 
and a product-specific interpretation of ``new drug'' underpins FDA's 
drug regulatory system.
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    \1\ For example, Elixir Sulfanilamide, a liquid version of 
sulfanilamide (an early antibiotic widely used in the 1930s and 
1940s to treat streptococcal infections), was responsible for the 
deaths of more than 100 people in 1937. The liquid formulation was 
manufactured using sulfanilamide as the active ingredient in a 
diethylene glycol-based solution. Had the manufacturer conducted an 
animal study or a review of then-existing scientific journals, it 
would have revealed the highly toxic nature of the inactive 
ingredient diethylene glycol, but Federal law at the time did not 
require such studies, nor did it require premarket review of the 
drug by FDA. This tragedy spurred Congress to enact the FD&C Act in 
1938, which required that new drugs be approved by FDA for safety 
before they could be marketed. Another example occurred in 1983, 
when 38 premature infants died and 43 were seriously injured after 
being intravenously administered E-Ferol, an unapproved high potency 
form of vitamin E. Injectable vitamin E drugs for use in premature 
infants had been marketed since at least 1949; however, E-Ferol was 
a new formulation, containing higher levels of vitamin E and using a 
relatively high concentration of two polysorbates as emulsifiers, 
which subsequent research suggests were likely responsible for the 
injuries and deaths of the premature infants.
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    FDA has long employed a risk-based enforcement approach with 
respect to new drugs marketed without an approved application. In 
October 2003, the Agency published a draft guidance, entitled 
``Marketed Unapproved Drugs--Compliance Policy Guide,'' to clarify how 
FDA generally intended to exercise its enforcement discretion regarding 
illegally marketed unapproved new drugs (October 23, 2003, 68 FR 
60702). In June 2006, FDA finalized the 2003 draft guidance in a final 
guidance entitled ``Marketed Unapproved Drugs--Compliance Policy Guide 
Sec. 440.100, Marketed New Drugs Without Approved NDAs or ANDAs'' (CPG 
440.100 guidance) (June 9, 2006, 71 FR 33466). The CPG 440.100 guidance 
described how FDA intended to prioritize regulatory action under its 
existing enforcement authority regarding currently marketed unapproved 
new drugs, including that FDA generally intended to apply a risk-based 
approach.
    In 2011, FDA updated the CPG 440.100 guidance to clarify that 
unapproved new drugs introduced onto the market after September 19, 
2011, were subject to enforcement action at any time without regard to 
the enforcement priorities set out in CPG 440.100 (September 21, 2011, 
76 FR 58398). As described in the updated version of the CPG 440.100 
guidance, FDA generally intended to encourage manufacturers of 
unapproved new drugs to submit applications for their products, while 
continuing to apply a risk-based approach to removing unapproved new 
drugs from the market and preserving access to medically necessary 
drugs.
    The CPG 440.100 guidance was part of FDA's UDI, which focuses on 
addressing the continued illegal marketing in the United States of drug 
products that lack the required FDA review and approval for safety and 
efficacy. To address this problem, FDA's UDI adopts a risk-based 
approach for removing from the market unapproved new drugs, 
particularly those that pose serious risks to patients, with the goal 
of also preserving patient access to medically necessary drugs and 
encouraging manufacturers of unapproved new drugs to submit 
applications for their products. The UDI has a two-pronged approach to 
help assure patient safety. First, the Agency encourages manufacturers 
of unapproved new drugs to obtain approval to be legally marketed in 
the United States. Second, FDA works to remove unapproved new drugs 
from the

[[Page 28607]]

market consistent with risk-based enforcement priorities and existing 
enforcement authorities.
    As a result of the UDI, FDA has initiated 45 actions since 2006 
(some affecting multiple unapproved new drugs) that have led to 
hundreds of potentially unsafe drugs being voluntarily removed from the 
market, including several drugs with significant safety concerns. These 
drugs were removed from the market in response to FDA Federal Register 
notices announcing that FDA intended to take enforcement action (13 of 
the actions), warning letters (15 of the actions), or at FDA's informal 
request through communications such as a teleconference (17 of the 
actions). In all 45 actions, safety concerns supported removal of the 
unapproved new drug products from the market, such as serious adverse 
events, labeling that did not adequately warn healthcare professionals 
of risks, or potential risks of harm resulting from adulterated drugs 
produced by facilities with current good manufacturing practice 
violations.
    The following are well-documented examples of significant adverse 
events associated with unapproved new drugs that resulted in compliance 
actions to remove an entire class of unapproved new drugs from the 
market. As noted below, these compliance actions have also spurred 
manufacturers to seek and obtain FDA approval of safe and effective 
versions of these drugs:
     Carbinoxamine-containing products
    [cir] Between 1983 and 2006, FDA became aware of 21 deaths in 
children under 2 years of age associated with the use of carbinoxamine-
containing drugs, including unapproved drugs. FDA had concerns about 
the risks associated with these products because, although their safety 
and effectiveness had not been studied in infants and young children, 
they were promoted for use in this vulnerable age group. As a result, 
in June 2006, FDA issued a Federal Register notice announcing that it 
intended to take enforcement action against unapproved drug products 
containing carbinoxamine and those who cause the manufacture of such 
products.\2\ As of February 2021, six FDA-approved carbinoxamine-
containing drug products, including five generic versions, are 
available on the marketplace and are labeled as contraindicated in 
children under 2 years old.
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    \2\ 71 FR 33462 (June 9, 2006). See https://www.govinfo.gov/content/pkg/FR-2006-06-09/pdf/E6-9033.pdf.
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     Quinine
    [cir] Between 1969 and 2006, FDA received 665 adverse events 
reports, including 93 deaths, associated with unapproved quinine 
sulfate use. Among the more common types of events with serious 
outcomes reported to the Agency were cardiac events, renal failure, and 
events related to overdose. FDA approved its first quinine sulfate 
product in August 2005, and the approved labeling for quinine sulfate 
provides extensive warnings to ensure its safe use. After a safe and 
effective FDA-approved quinine sulfate product became available, in 
December 2006, FDA issued a Federal Register notice announcing that it 
intended to take enforcement action against unapproved drug products 
containing quinine (including quinine sulfate and other salts of 
quinine) and persons who cause the manufacture of such products or 
their shipment in interstate commerce because these products presented 
serious safety risks that the unapproved drug labeling did not 
comprehensively describe.\3\ As of February 2021, there are five FDA-
approved quinine sulfate capsules, including four generic drug 
products, available in the marketplace.
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    \3\ 71 FR 75557 (December 15, 2006). See https://www.govinfo.gov/content/pkg/FR-2006-12-15/pdf/06-9713.pdf.
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    As noted above, these compliance actions have resulted in 
potentially unsafe unapproved new drugs being removed from the market 
as well as FDA approval of safe and effective versions of drug products 
previously marketed without approval. Approval of formerly unapproved 
new drugs helps reduce concerns about a potential market disruption or 
shortage of these drugs, because the manufacturers of approved drugs 
have invested in a manufacturing process that helps to ensure the drug 
is produced reliably and consistently. This lowers the risk of quality 
problems, which are one of the main causes of shortages.\4\ In 
addition, the approval of previously unapproved new drugs assures the 
American public that the approved versions of those drugs are safe and 
effective for their intended uses, manufactured in accordance with 
Federal quality standards, and bear accurate and complete information 
in their labeling regarding risks, benefits, and safe use.
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    \4\ FDA, Drug Shortages: Root Causes and Potential Solutions 
(2019), available at https://www.fda.gov/media/131130/download.
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    On November 25, 2020, HHS published the HHS Notice in the Federal 
Register stating that it was ``terminating'' the UDI by withdrawing 
FDA's CPG 440.100 guidance, effective 30 days from the publication 
date. HHS also issued a request for information regarding the 
definition of ``new drug'' under section 201(p) of the FD&C Act and 
whether certain drugs might be grandfathered or qualify as GRASE and 
therefore would not be subject to the new drug approval requirement. We 
did not find any evidence that HHS consulted with, otherwise involved, 
or even notified FDA before issuing the HHS Notice. Section 1003(d) of 
the FD&C Act (21 U.S.C. 393(d)) provides that the Secretary ``shall be 
responsible for executing'' the FD&C Act ``through the [FDA] 
Commissioner.'' Here, the HHS Notice in withdrawing the CPG 440.100 
guidance is clearly an action ``executing'' the FD&C Act.
    The HHS Notice misinterprets the statutory term ``new drug.'' 
First, the HHS Notice erroneously suggests that FDA has taken the 
position that drug substances (i.e., active ingredients) marketed prior 
to June 25, 1938, could be ``grandfathered'' under the statute, and 
therefore, are not ``new drugs'' subject to FDA's new drug approval 
process. As explained above, FDA has long interpreted the word ``drug'' 
in ``new drug'' to refer to the entire drug product and not just the 
active ingredient, and the U.S. Supreme Court has ruled that this is 
the correct interpretation of that term. Consistent with this product-
specific interpretation of ``new drug,'' FDA has construed the 
grandfather clause in section 201(p)(1) of the FD&C Act to mean that a 
drug product cannot be grandfathered if it differs in any respect from 
the pre-1938 version of the drug product. Second, the HHS Notice 
erroneously suggests that FDA had interpreted the definition of ``new 
drug'' to exclude drug products with active ingredients marketed prior 
to June 25, 1938, but that FDA failed to acknowledge this 
interpretation in the CPG 440.100 guidance, as part of the UDI. In 
fact, the CPG 440.100 guidance did not change FDA's interpretation of 
``new drug;'' the CPG reflected the interpretation that the Agency had 
applied for decades and that was upheld by the U.S. Supreme Court in 
1983.
    The HHS Notice also includes other misstatements, including 
erroneously describing the UDI and FDA's CPG 440.100 guidance as a new 
policy that should have been adopted through notice-and-comment 
rulemaking. However, the CPG 440.100 guidance did not change FDA's 
interpretation of ``new drug,'' ``grandfathered,'' or ``GRASE.'' 
Instead, it described FDA's enforcement priorities under FDA's existing 
legal authorities regarding illegally marketed unapproved new drugs. 
Communicating enforcement policies through guidance documents rather 
than legislative rules is consistent with both the

[[Page 28608]]

Administrative Procedure Act (APA; 5 U.S.C. 551 et seq.) and FDA's 
regulations on good guidance practices (Sec.  10.115 (21 CFR 10.115)). 
Under the APA, FDA may use guidance documents to ``advise the public 
prospectively of the manner in which the agency proposes to exercise a 
discretionary power.'' \5\ Accordingly, FDA's good guidance practice 
regulations define ``guidance documents'' to include ``documents that 
relate to . . . enforcement policies.'' (Sec.  10.115(b)(2)).
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    \5\ See the Attorney General's Manual on the APA (1947), at 30 
n.3.
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    Additionally, the HHS Notice is supported by flawed facts. It 
cites, for the proposition that the UDI and CPG 440.100 guidance 
resulted in price increases for certain new drugs, only a single 
observational study of 26 products, which included pricing estimates 
that were not inflation-adjusted over the 4-year observational period, 
which could lead to an overestimation of real price changes.\6\ The HHS 
Notice also erroneously ties the 2015 price increase for the drug 
DARAPRIM to the UDI. DARAPRIM was approved as a new drug under the FD&C 
Act in 1953. Following the 1962 FD&C Act amendments, which required 
drugs to demonstrate not only safety but efficacy, DARAPRIM was found 
to be effective, in 1971, as part of FDA's review of all new drugs that 
had been approved only for safety before 1962. DARAPRIM was then fully 
approved by FDA as a safe and effective drug. For years after its 
approval, DARAPRIM was an off-patent, off-exclusivity drug eligible for 
generic competition, but no drug manufacturer sought and obtained 
approval of a generic version during this period. It was during this 
period, in 2015, that the holder of the approved application for 
DARAPRIM significantly raised the price of the drug. FDA recently 
approved a generic version of this product on February 28, 2020.\7\
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    \6\ See R. Gupta et al., ``The FDA Unapproved Drugs Initiative: 
An Observational Study of the Consequences for Drug Prices and 
Shortages in the United States,'' 23 Journal of Managed Care & 
Specialty Pharmacy 1066 (October 2017) (the Yale Study). Of note, 
the authors of the Yale Study suggested ways to mitigate unintended 
consequences of the UDI that did not include terminating the UDI by 
withdrawing CPG 440.100 guidance or reinterpreting the definition of 
``new drug.''
    \7\ FDA continues to maintain efforts to improve the efficiency 
of the generic drug development, review, and approval process, 
generally, and it prioritizes the review of submissions for generic 
drugs for which there are fewer than three approved generic versions 
for the reference listed drug (RLD) and for which there are no 
blocking patents or exclusivities on the RLD.
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    Due to the HHS Notice's legal and factual inaccuracies, including 
those described above, HHS and FDA believe it is appropriate to 
withdraw the HHS Notice at this time. The HHS Notice does not 
accurately reflect the Department's or FDA's thinking because it is 
inconsistent with the FD&C Act, FDA regulations, and judicial 
precedent, among other legal authorities, and is not supported by the 
facts. In addition, the HHS Notice could result in significant harm to 
public health by suggesting that unsafe or ineffective drugs could 
circumvent the drug approval process.
    Although the withdrawal of FDA's CPG 440.100 guidance does not 
change the legal obligations that apply to new drugs, or FDA's existing 
enforcement authority over unapproved new drugs, we recognize that the 
withdrawal of the CPG may have created confusion for the public, 
including regulated industry, as to how FDA intends to prioritize its 
enforcement resources in this area. FDA therefore plans to issue 
guidance on this topic consistent with good guidance practices. The 
guidance will provide appropriate updates regarding FDA's enforcement 
priorities for marketed unapproved new drugs. In the interim, before 
such guidance is issued, FDA will continue to exercise its existing 
general approach to prioritizing regulatory and enforcement action, 
which involves risk-based prioritization in light of all the facts of a 
given circumstance. Risk-based enforcement best supports FDA's public 
health priorities.
    FDA's longstanding interpretation of the statutory terms ``new 
drug,'' ``grandfathered,'' and ``GRASE'' are unchanged and the HHS 
Notice did not affect the requirements that apply to new drugs under 
the statutes FDA administers. The HHS Notice did not, and legally could 
not, provide a new pathway for the legal marketing of unapproved new 
drugs. Neither HHS nor FDA has the authority to exempt a product or 
class of products that are new drugs under the FD&C Act from the new 
drug approval requirements of the FD&C Act. See Cutler v. Kennedy, 475 
F. Supp. 838, 856 (D.D.C. 1979); Hoffman-LaRoche v. Weinberger, 425 F. 
Supp. 890, 892-894 (D.D.C. 1975).

    Dated: May 17, 2021.
Janet Woodcock,
Acting Commissioner of Food and Drugs.
    Dated: May 20, 2021.
Xavier Becerra,
Secretary, Department of Health and Human Services.
[FR Doc. 2021-11257 Filed 5-26-21; 8:45 am]
BILLING CODE 4164-01-P


