[Federal Register Volume 78, Number 219 (Wednesday, November 13, 2013)]
[Proposed Rules]
[Pages 67985-67999]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2013-26799]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 314 and 601

[Docket No. FDA-2013-N-0500]
RIN 0910-AG94


Supplemental Applications Proposing Labeling Changes for Approved 
Drugs and Biological Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA or the Agency) is 
proposing to amend its regulations to revise and clarify procedures for 
application holders of an approved drug or biological product to change 
the product labeling to reflect certain types of newly acquired 
information in advance of FDA's review of the change. The proposed rule 
would create parity among application holders with respect to such 
labeling changes by permitting holders of abbreviated new drug 
applications (ANDAs) to distribute revised product labeling that 
differs in certain respects, on a temporary basis, from the labeling of 
its reference listed drug (RLD) upon submission to FDA of a ``changes 
being effected'' (CBE-0) supplement. The proposed rule describes the 
process by which information regarding a CBE-0 labeling supplement 
submitted by a new drug application (NDA) holder, an ANDA holder, or a 
biologics license application (BLA) holder would be made publicly 
available during FDA's review of the labeling change and clarifies 
requirements for all ANDA holders to submit conforming labeling 
revisions after FDA has taken an action on the NDA or ANDA holder's 
CBE-0 labeling supplement. The proposed rule also would amend the 
regulations to allow submission of a CBE-0 labeling supplement for 
certain changes to the ``Highlights of Prescribing Information'' for 
drug products with labeling in the ``Physician Labeling Rule'' (PLR) 
format.

DATES: Submit either electronic or written comments on the proposed 
rule by January 13, 2014. See section VII for the proposed effective 
date of a final rule based on this proposed rule. Submit comments on 
information collection issues under the Paperwork Reduction Act of 1995 
(the PRA) by December 13, 2013, (see the ``Paperwork Reduction Act of 
1995'' section of this document).

ADDRESSES: You may submit comments, identified by Docket No. FDA-2013-
N-0500 and/or Regulatory Information Number (RIN) 0910-AG94, by any of 
the following methods, except that comments on information collection 
issues under the PRA must be submitted to the Office of Information and 
Regulatory Affairs, Office of Management and Budget (OMB) (see the 
``Paperwork Reduction Act of 1995'' section of this document).

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.

Written Submissions

    Submit written submissions in the following ways:
     Mail/Hand delivery/Courier (for paper or CD-ROM 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the Agency name 
and Docket No. FDA-2013-N-0500 and RIN 0910-AG94 for this rulemaking. 
All comments received may be posted without change to http://www.regulations.gov, including any personal information provided. For 
additional information on submitting comments, see the ``Comments'' 
heading of the SUPPLEMENTARY INFORMATION section.
    Docket: For access to the docket to read background documents or 
comments received, go to http://www.regulations.gov and insert the 
docket number(s), found in brackets in the heading of this document, 
into the ``Search'' box and follow the prompts and/or go to the 
Division of Dockets Management, 5630 Fishers Lane, rm. 1061, Rockville, 
MD 20852.

FOR FURTHER INFORMATION CONTACT: Janice L. Weiner, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, rm. 6304, Silver Spring, MD 20993-0002, 301-
796-3601.

SUPPLEMENTARY INFORMATION: 

Table of Contents

I. Background
    A. Drug Labeling
    B. Current Requirements Related to Changes to Approved Drug 
Labeling
    C. Specific Labeling Requirements Related to Generic Drugs
    D. Recent Court Decisions
II. Description of the Proposed Rule
    A. Supplement Submission for Safety-Related Labeling ``Changes 
Being Effected'' (Proposed Sec. Sec.  314.70(b)(2), (c)(6), and 
(c)(8) and 601.12(f)(2))
    B. Approval of Supplements to an Approved ANDA for a Labeling 
Change (Proposed Sec.  314.97(b))
    C. Exception for ANDA Labeling Differences Resulting From 
``Changes Being Effected'' Supplement (Proposed Sec.  
314.150(b)(10)(iii))
III. Legal Authority
IV. Analysis of Impacts
V. Paperwork Reduction Act of 1995
VI. Environmental Impact
VII. Effective Date
VIII. Federalism
IX. Request for Comments
X. References

Executive Summary

Purpose of the Regulatory Action

    The Federal Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 
301 et seq.) and the Public Health Service Act (the PHS Act) (42 U.S.C. 
201 et seq.) provide FDA with authority over the labeling for drugs and 
biological products, and authorize the Agency to enact regulations to 
facilitate FDA's review and approval of applications regarding the 
labeling for those products. FDA is proposing to amend its regulations 
to revise and clarify procedures for application holders to change the 
labeling of an approved drug or biological product to reflect certain 
types of newly acquired information in advance of FDA's review of the 
change through a CBE-0 supplement. The proposed rule would create 
parity among application holders with respect to these safety-related 
labeling changes by permitting ANDA holders to distribute revised 
generic drug labeling that differs in certain respects, on a temporary 
basis, from the RLD labeling upon submission to FDA of a CBE-0 
supplement.

[[Page 67986]]

Summary of the Major Provisions of the Regulatory Action

    The proposed rule would enable ANDA holders to update product 
labeling promptly to reflect certain types of newly acquired 
information related to drug safety, irrespective of whether the revised 
labeling differs from that of the RLD. An ANDA holder would be required 
to send notice of the labeling change proposed in the CBE-0 supplement, 
including a copy of the information supporting the change, to the NDA 
holder for the RLD at the same time that the supplement to the ANDA is 
submitted to FDA, unless approval of the NDA has been withdrawn. This 
proposal would ensure that the NDA holder for the RLD is promptly 
advised of the newly acquired information that was considered to 
warrant the labeling change proposed for the drug in the CBE-0 
supplement.
    If approval of the NDA for the RLD has been withdrawn (for reasons 
other than safety or effectiveness), FDA's evaluation of the labeling 
change proposed by the ANDA holder would consider any submissions 
related to the proposed labeling change from any other application 
holder for drug products containing the same active ingredient.
    To make the safety-related changes to drug labeling described in a 
CBE-0 supplement readily available to prescribing health care providers 
and the public while FDA is reviewing the supplement, FDA proposes to 
establish a dedicated Web page (or, alternatively, to modify an 
existing FDA Web page) on which FDA would promptly post information 
regarding the labeling changes proposed in a CBE-0 supplement.
    A supplement to an approved ANDA for a safety-related labeling 
change that is submitted in a prior approval supplement or in a CBE-0 
supplement would be approved upon approval of the same labeling change 
for the RLD. The proposed rule would establish a 30-day timeframe in 
which all ANDA holders would be required to submit a CBE-0 supplement 
with conforming labeling changes after FDA approval of a revision to 
the labeling for the RLD.
    The proposed rule also would amend the regulations to allow 
submission of a CBE-0 labeling supplement for certain changes to the 
``Highlights of Prescribing Information'' for drug products with 
labeling in the PLR format. This is intended to remove an unnecessary 
impediment to prompt communication of the most important safety-related 
labeling changes (e.g., boxed warnings and contraindications) for drug 
products with labeling in the PLR format.
    Finally, FDA regulations provide that FDA may take steps to 
withdraw approval of an ANDA if the generic drug labeling is no longer 
consistent with the labeling for the RLD, subject to certain exceptions 
specified in the regulations. The proposed rule would amend the 
regulations to add a new exception for generic drug labeling that is 
temporarily inconsistent with the labeling for the RLD due to safety-
related labeling changes submitted by the ANDA holder in a CBE-0 
supplement.

Costs and Benefits

    The economic benefits to the public health from adoption of the 
proposed rule are not quantified. By allowing all application holders 
to update labeling based on newly acquired information that meets the 
criteria for a CBE-0 supplement, communication of important drug safety 
information to prescribing health care providers and the public could 
be improved. The primary estimate of the costs of the proposed rule 
includes costs to ANDA and NDA holders for submitting and reviewing 
CBE-0 supplements. The Agency estimates the net annual social costs to 
be between $4,237 and $25,852. The present discounted value over 20 
years would be in the range of $63,040 to $384,616 at a 3 percent 
discount rate, and in the range of $44,890 to $273,879 at a 7 percent 
discount rate.

I. Background

A. Drug Labeling

    Under the FD&C Act, the PHS Act, and FDA regulations, the Agency 
makes decisions regarding the approval of marketing applications, 
including supplemental applications, based on a comprehensive analysis 
of the product's risks and benefits under the conditions of use 
prescribed, recommended, or suggested in the labeling (see 21 U.S.C. 
355(d); 42 U.S.C. 262).
    FDA-approved drug labeling summarizes the essential information 
needed for the safe and effective use of the drug,\1\ and reflects 
FDA's finding regarding the safety and effectiveness of the drug under 
the labeled conditions of use. The primary purpose of labeling 
(commonly referred to as the ``package insert'' or ``prescribing 
information'') for prescription drugs is to provide health care 
practitioners with the essential scientific information needed to 
facilitate prescribing decisions, thereby enhancing the safe and 
effective use of prescription drug products and reducing the likelihood 
of medication errors. Prescription drug labeling is directed to health 
care practitioners, but may include FDA-approved patient labeling (see 
Sec.  201.57(c)(18) (21 CFR 201.57(c)(18)) and 21 CFR 201.80(f)(2)). 
The over-the-counter (OTC) Drug Facts labeling is directed to consumers 
and conveys information in a clear, standardized format to enable 
patient self-selection of an appropriate drug and enhance the safe and 
effective use of the drug (see 21 CFR 201.66).
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    \1\ For the purposes of this document, unless otherwise 
specified, references to ``drugs'' or ``drug products'' include 
drugs approved under the FD&C Act and biological products licensed 
under the PHS Act, other than biological products that also meet the 
definition of a device in section 201(h) of the FD&C Act (21 U.S.C. 
321(h)).
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    All drugs have risks, and health care practitioners and patients 
must balance the risks and benefits of a drug when making decisions 
about medical therapy. As a drug is used more widely or under diverse 
conditions, new information regarding the risks and benefits of a drug 
may become available. This may include new risks or new information 
about known risks. Accordingly, all holders of NDAs, ANDAs, and BLAs 
are required to develop written procedures for the surveillance, 
receipt, evaluation, and reporting of postmarketing adverse drug 
experiences to FDA (see Sec. Sec.  314.80(b), 314.98(a), and 600.80(b) 
(21 CFR 314.80(b), 314.98(a), and 600.80(b)). Application holders must 
promptly review all adverse drug experience information obtained or 
otherwise received by the applicant from any source, foreign or 
domestic, including information derived from commercial marketing 
experience, postmarketing clinical investigations, postmarketing 
epidemiological/surveillance studies, reports in the scientific 
literature, and unpublished scientific papers, and comply with 
applicable reporting and recordkeeping requirements (see Sec. Sec.  
314.80(b), 314.98(a), and 600.80(b)). Application holders also must 
comply with requirements for other postmarketing reports under Sec.  
314.81 (21 CFR 314.81) and 21 CFR 600.81 and section 505(k) of the FD&C 
Act (21 U.S.C. 355(k)). These requirements include submission of an 
annual report (including a brief summary of significant new information 
from the previous year that might affect the safety, effectiveness, or 
labeling of the drug product, and a description of actions the 
applicant has taken or intends to take as a result of this new 
information) and, if appropriate, proposed revisions to product 
labeling (see Sec.  314.81).
    When new information becomes available that causes information in 
labeling to be inaccurate, the

[[Page 67987]]

application holder must take steps to change the content of its 
labeling, in accordance with Sec. Sec.  314.70, 314.97, and 601.12 (21 
CFR 314.70, 314.97, and 601.12). All holders of marketing applications 
for drug products have an ongoing obligation to ensure their labeling 
is accurate and up-to-date. A drug is misbranded in violation of the 
FD&C Act when its labeling is false or misleading, or does not provide 
adequate directions for use and adequate warnings (see 21 U.S.C. 331(a) 
and (b) and 352(a), (f), and (j)).

B. Current Requirements Related to Changes to Approved Drug Labeling

    For most substantive changes to product labeling, an application 
holder is required to submit a prior approval supplement and receive 
FDA approval for the change (see Sec. Sec.  314.70(b) and 
601.12(f)(1)). However, in the interest of public health, the 
regulations permit certain labeling changes based on newly acquired 
information about an approved drug to be implemented upon receipt by 
the Agency of a supplemental application that includes the change. 
These supplements are commonly referred to as ``changes being effected 
supplements'' or ``CBE-0 supplements'' (see Sec. Sec.  
314.70(c)(6)(iii) and 601.12(f)(2)).
    The current regulations provide that application holders may submit 
CBE-0 supplements for the following types of changes to product 
labeling:
     To add or strengthen a contraindication, warning, 
precaution, or adverse reaction for which the evidence of a causal 
association satisfies the standard for inclusion in the labeling under 
Sec.  201.57(c);
     To add or strengthen a statement about drug abuse, 
dependence, psychological effect, or overdosage;
     To add or strengthen an instruction about dosage and 
administration that is intended to increase the safe use of the drug 
product;
     To delete false, misleading, or unsupported indications 
for use or claims for effectiveness; or
     Any labeling change normally requiring a supplement 
submission and approval prior to distribution of the drug product that 
FDA specifically requests be submitted under this provision.
    The CBE-0 supplement procedures originated from a 1965 policy based 
on FDA's enforcement discretion regarding certain labeling changes that 
should be placed into effect ``at the earliest possible time'' (see 
``Supplemental New-Drug Applications,'' 30 FR 993, January 30, 1965). 
Over the years, FDA has clarified the types of labeling changes that 
may be made by a CBE-0 supplement through a series of rulemakings.
    In 1985, FDA updated its procedures for CBE-0 supplements and 
emphasized that CBE-0 supplements were intended as a narrow exception 
to the general rule that labeling changes require FDA's prior approval 
(see ``New Drug and Antibiotic Regulations''; final rule, 50 FR 7452 at 
7470, February 22, 1985).
    In 2006, FDA amended its regulations governing the content and 
format of prescription drug labeling to require, among other things, 
that the labeling of new and recently approved products include 
introductory prescribing information titled ``Highlights of Prescribing 
Information'' (see 21 CFR 201.57(a); see also ``Requirements on Content 
and Format of Labeling for Human Prescription Drug and Biological 
Products''; final rule, 71 FR 3922, January 24, 2006). The ``Highlights 
of Prescribing Information'' (Highlights) is intended to summarize the 
information that is most important for prescribing the drug safely and 
effectively, and to organize the information into logical groups to 
enhance accessibility, retention, and access to the more detailed 
information (see 71 FR 3922 at 3931). As part of this rulemaking, FDA 
amended the CBE-0 labeling supplement provisions to exclude most 
changes to the information required in the Highlights, which must be 
made by a prior approval supplement unless FDA specifically requests 
that the labeling change be submitted in a CBE-0 supplement or FDA 
grants a waiver request under Sec.  314.90 (21 CFR 314.90).
    In 2008, FDA amended the regulations governing CBE-0 supplements to 
codify the Agency's view that a CBE-0 labeling supplement is 
appropriate only to reflect newly acquired information and to clarify 
that a CBE-0 supplement may be used to add or strengthen a 
contraindication, warning, precaution, or adverse reaction only if 
there is sufficient evidence of a causal association with the approved 
product. FDA explained that these requirements are intended to help 
ensure that scientifically accurate information appears in the approved 
labeling for such products (``Supplemental Applications Proposing 
Labeling Changes for Approved Drugs, Biologics, and Medical Devices''; 
final rule, 73 FR 49603 at 49604, August 22, 2008).
    FDA carefully reviews any labeling change proposed in a CBE-0 
supplement, as well as the underlying information or data supporting 
the change. FDA has the authority to accept, reject, or request 
modifications to the proposed changes as the Agency deems appropriate, 
and has the authority to bring an enforcement action if the added 
information makes the labeling false or misleading (see 21 U.S.C. 
352(a)). If the newly acquired information changes the benefit/risk 
balance for the drug, such that the product no longer meets FDA's 
standard for approval, then FDA will take appropriate action (see 21 
U.S.C. 355(e) and 355-1).
    The CBE-0 supplement regulations allow application holders to 
comply with the requirement to update labeling promptly to include a 
warning about a clinically significant hazard as soon as there is 
reasonable evidence of a causal association with a drug (Sec.  
201.57(c)(6)), and other risk information as required by the 
regulations (Sec. Sec.  201.57(c) and 201.100(d)(3)).

C. Specific Labeling Requirements Related to Generic Drugs

    The FD&C Act describes different routes for obtaining approval of 
two broad categories of drug applications: An NDA containing full 
reports of investigations of safety and effectiveness, for which the 
requirements are set out in section 505(b) and (c) of the FD&C Act, and 
an ANDA, for which the requirements are set out in section 505(j).
    The ANDA category can be further subdivided into an ANDA and a 
``petitioned ANDA.'' An ANDA must contain information to show that the 
proposed drug product is the same as a drug previously approved under 
section 505(c) of the FD&C Act (the RLD) with respect to active 
ingredient(s), dosage form, route of administration, strength, 
labeling, and conditions of use, among other characteristics, and is 
bioequivalent to the RLD. An applicant that can meet the requirements 
under section 505(j) of the FD&C Act for approval may rely upon the 
Agency's finding of safety and effectiveness for the RLD and need not 
repeat the extensive nonclinical and clinical investigations required 
for approval of an NDA submitted under section 505(b)(1) of the FD&C 
Act. A ``petitioned ANDA'' is a type of ANDA for a drug that differs 
from a previously approved drug product in dosage form, route of 
administration, strength, or active ingredient (in a product with more 
than one active ingredient), for which FDA has determined, in response 
to a suitability petition submitted under section 505(j)(2)(C) of the 
FD&C Act, that clinical studies are not necessary to demonstrate safety 
and effectiveness.
    A generic drug is classified as therapeutically equivalent to the 
RLD if it is a pharmaceutical equivalent and has demonstrated 
bioequivalence (see

[[Page 67988]]

``Approved Drug Products With Therapeutic Equivalence Evaluations'' 
(the Orange Book), 33rd ed., 2013, p. vii). The generic drug program is 
based on the principle that ``products classified as therapeutically 
equivalent can be substituted with the full expectation that the 
substituted product will produce the same clinical effect and safety 
profile as the prescribed product'' (Orange Book, 33rd ed., 2013, p. 
vii). Currently, approximately 80 percent of all drugs dispensed are 
generic drugs (Ref. 1). After the introduction of a generic drug, the 
market share of the ``brand name'' drug (i.e., the drug approved in an 
NDA under section 505(c) of the FD&C Act) may drop substantially. Among 
drugs for which a generic version is available, approximately 94 
percent are dispensed as a generic (Ref. 1). For any given brand name 
drug, there may be multiple approved generic drugs, and the prescribing 
health care provider ordinarily would not know which generic drug may 
be substituted for the prescribed product under applicable State law.
    A generic drug is required to have the same labeling as the RLD at 
the time of approval, except for changes required because of 
differences approved under a suitability petition (see section 
505(j)(2)(C) of the FD&C Act and 21 CFR 314.93) or because the drug 
product and the RLD are produced or distributed by different 
manufacturers (see section 505(j)(2)(A)(v) of the FD&C Act). FDA has 
described those differences in Sec.  314.94(a)(8)(iv) (21 CFR 
314.94(a)(8)(iv)) as including, for example, differences in 
formulation, bioavailability, or pharmacokinetics; labeling revisions 
made to comply with current FDA labeling guidelines or other guidance; 
or omission of an indication or other aspect of labeling protected by 
patent or exclusivity. FDA has generally taken the position that a 
generic drug must maintain the same labeling as the RLD throughout the 
lifecycle of the generic drug product (see Sec.  314.150(b)(10) (21 CFR 
314.150(b)(10)). Thus, if an ANDA holder believes that newly acquired 
safety information should be added to its product labeling, it should 
provide adequate supporting information to FDA, and FDA will determine 
whether the labeling for the generic drug(s) and the RLD should be 
revised (see 57 FR 17950 at 17961; April 28, 1992).
    Although FDA has expressed differing views on this issue over the 
years, FDA generally has advised that an ANDA holder may use the CBE-0 
supplement process only to update its product labeling to conform with 
approved labeling for the RLD or to respond to FDA's specific request 
to submit a labeling change under this provision, and may not 
unilaterally change ANDA labeling in a manner that differs from the RLD 
(see Sec.  314.150(b)(10); see also 57 FR 17950 at 17961, and 
``Supplemental Applications Proposing Labeling Changes for Approved 
Drugs, Biologics, and Medical Devices''; proposed rule, 73 FR 2848 at 
2849; footnote 1; January 16, 2008).
    At the time of FDA's adoption of the generic drug regulations in 
1992, FDA believed it was important that product labeling for the RLD 
and any generic drugs be the same to assure physicians and patients 
that generic drugs were, indeed, equivalent to their RLD. However, as 
the generic drug industry has matured and captured an increasing share 
of the market, tension has grown between the requirement that a generic 
drug have the same labeling as its RLD, which facilitates substitution 
of a generic drug for the prescribed product, and the need for an ANDA 
holder to be able to independently update its labeling as part of its 
independent responsibility to ensure that the labeling is accurate and 
up-to-date. In the current marketplace, in which approximately 80 
percent of drugs dispensed are generic and, as we have learned, brand 
name drug manufacturers may discontinue marketing after generic drug 
entry, FDA believes it is time to provide ANDA holders with the means 
to update product labeling to reflect data obtained through 
postmarketing surveillance, even though this will result in temporary 
labeling differences among products. In a study of FDA safety-related 
drug labeling changes made in 2010, FDA found that the median time from 
initial approval of the drug product to the time of making the safety-
related labeling change was 11 years, which confirms that data 
supporting labeling changes may become available after approval of 
generic versions of the drug product (see Ref. 2). FDA found that 
``[t]he most critical safety-related label changes, boxed warnings and 
contraindications, occurred a median 10 and 13 years after drug 
approval (and the range spanned from 2 to 63 years after approval), 
underscoring the importance of persistent and vigilant postmarket drug 
safety surveillance'' (Ref. 2).

D. Recent Court Decisions

    In two recent cases, the United States Supreme Court considered the 
issue of whether Federal law preempts State law tort claims against 
pharmaceutical manufacturers for failing to provide adequate warnings 
in drug product labeling (``failure-to-warn claims'') (see Pliva, Inc. 
v. Mensing, 131 S.Ct. 2567 (2011) and Wyeth v. Levine, 555 U.S. 555 
(2009)). In Pliva v. Mensing, the Court held that the difference 
between NDA and ANDA holders' ability to independently change product 
labeling through CBE-0 supplements leads to different outcomes on 
whether Federal labeling requirements preempt State law failure-to-warn 
claims. In Wyeth v. Levine, the Court decided that Federal law does not 
preempt a State law failure-to-warn claim that a brand name drug's 
labeling did not contain an adequate warning. The Court found that the 
drug manufacturer could have unilaterally added a stronger warning to 
product labeling under the CBE-0 regulation as applied to NDAs, and 
absent clear evidence that FDA would not have approved such a labeling 
change, it was not impossible for the manufacturer to comply with both 
Federal and State requirements. The Court reaffirmed that ``through 
many amendments to the [FD&C Act] and to FDA regulations, it has 
remained a central premise of federal drug regulation that the 
manufacturer bears responsibility for the content of its label at all 
times'' (555 U.S. at 570-571).
    Two years later, in Pliva v. Mensing, the Court decided that 
Federal law does preempt a State law failure-to-warn claim that a 
generic drug's labeling did not contain an adequate warning. The Court 
deferred to FDA's interpretation of its CBE-0 supplement and labeling 
regulations for ANDAs, and found that Federal law did not permit a 
generic drug manufacturer to use the CBE-0 supplement process to 
unilaterally strengthen warnings in its labeling or to issue additional 
warnings through ``Dear Health Care Professional'' letters, which FDA 
``argues . . . qualify as 'labeling' '' (131 S.Ct. at 2576). The Court 
found that, under the current regulatory scheme, it was impossible for 
a generic drug manufacturer to comply with its Federal law duty to have 
the same labeling as the RLD and satisfy its State law duty to provide 
adequate labeling (131 S.Ct. at 2578). In September 2011, Public 
Citizen petitioned the Agency to revise its regulations in response to 
the Mensing decision (see Docket No. FDA-2011-P-0675).
    As a result of the decisions in Wyeth v. Levine and Pliva v. 
Mensing, an individual can bring a product liability action for failure 
to warn against an NDA holder, but generally not an ANDA holder, and 
thus access to the courts is dependent on whether an individual is 
dispensed a brand name or generic drug. The Mensing decision alters the

[[Page 67989]]

incentives for generic drug manufacturers to comply with current 
requirements to conduct robust postmarketing surveillance, evaluation, 
and reporting, and to ensure that the labeling for their drugs is 
accurate and up-to-date.
    We are proposing to change our regulations to expressly provide 
that ANDA holders may distribute revised labeling that differs from the 
RLD upon submission of a CBE-0 supplement to FDA. FDA's proposed 
revisions to its regulations would create parity between NDA holders 
and ANDA holders with respect to submission of CBE-0 supplements for 
safety-related labeling changes based on newly acquired information. 
This proposal is also intended to ensure that generic drug companies 
actively participate with FDA in ensuring the timeliness, accuracy, and 
completeness of drug safety labeling in accordance with current 
regulatory requirements. If this proposed regulatory change is adopted, 
it may eliminate the preemption of certain failure-to-warn claims with 
respect to generic drugs.

II. Description of the Proposed Rule

A. Supplement Submission for Safety-Related Labeling ``Changes Being 
Effected'' (Proposed Sec. Sec.  314.70(b)(2), (c)(6), and (c)(8) and 
601.12(f)(2))

1. Equal Applicability to NDA Holders and ANDA Holders (Proposed Sec.  
314.70(c)(8))
    We are proposing to add Sec.  314.70(c)(8) to enable ANDA holders 
to submit a CBE-0 supplement for generic drug labeling that differs 
from the labeling of the RLD and to establish that Sec.  
314.70(c)(6)(iii) applies equally to the holder of an approved NDA or 
ANDA. Proposed Sec.  314.70(c)(8) states that an application holder may 
submit to its approved NDA or ANDA a supplement described by Sec.  
314.70(c)(6)(iii).
    If an NDA holder or ANDA holder obtains or otherwise receives newly 
acquired information that should be reflected in product labeling to 
accomplish any of the objectives specifically described in Sec.  
314.70(c)(6)(iii)(A) through (c)(6)(iii)(D), the NDA holder or ANDA 
holder must submit a CBE-0 supplement (see Sec.  314.70(c)(6)(iii); see 
also 21 CFR 314.3(b) (defining ``newly acquired information'')). As 
discussed in section I.A, all application holders, including ANDA 
holders, are required to conduct surveillance, evaluation, and 
reporting of postmarketing adverse drug experiences and, if warranted, 
to propose revisions to product labeling. Proposed Sec.  314.70(c)(8) 
would expressly permit ANDA holders to update product labeling promptly 
to reflect newly acquired information that meets the criteria described 
in Sec.  314.70(c)(6)(iii)(A) through (c)(6)(iii)(D) irrespective of 
whether the revised labeling differs from that of the RLD. In addition, 
if an ANDA holder submits a CBE-0 supplement for a labeling change that 
meets the criteria described in Sec.  314.70(c)(6)(iii)(A) through 
(c)(6)(iii)(E), the ANDA holder may distribute a ``Dear Health Care 
Provider'' letter (which also meets the statutory definition of 
``labeling'') regarding this labeling change in the same manner as an 
NDA holder or BLA holder, and be subject to the same statutory 
prohibition against marketing a misbranded product (see 21 U.S.C. 
321(m), 331(a) and (b), and 352, and 21 CFR 201.100(d)(1) and 
202.1(l)(2)). A ``Dear Health Care Provider'' letter may be used to 
disseminate the important new drug safety information that warranted 
the CBE-0 supplement, for example, a significant hazard to health or 
other important change in product labeling (see 21 CFR 200.5). FDA will 
continue to undertake any communication plans to health care providers 
(including distribution of ``Dear Health Care Provider'' letters) that 
are part of Risk Evaluation and Mitigation Strategies (REMS) that 
include one or more generic drugs (see 21 U.S.C. 355-1(i)(2)).
    The obligation to ensure that labeling is accurate and up-to-date 
applies equally to all ANDA holders. In certain circumstances, if the 
RLD approved under section 505(c) of the FD&C Act has been withdrawn 
from the market, FDA may select a drug product approved in an ANDA 
(including a petitioned ANDA) to be the ``reference standard'' that an 
applicant seeking approval of an ANDA that relies upon the withdrawn 
RLD must use in conducting an in vivo bioequivalence study required for 
approval (see 57 FR 17950 at 17954). However, the duty to maintain 
accurate product labeling does not differ between an ANDA designated as 
the reference standard for bioequivalence studies and other approved 
ANDAs.
    FDA acknowledges that there may be concerns about temporary 
differences in safety-related labeling for drugs that FDA has 
determined to be therapeutically equivalent, especially if multiple 
ANDA holders submit CBE-0 supplements with labeling changes that differ 
from each other and from the RLD. FDA also recognizes that health care 
practitioners are unlikely to review product labeling for each of the 
generic drugs that may be substituted for the prescribed product when 
making treatment decisions with their patients based on the balance of 
potential benefits and risks of the drug product for that patient. To 
address these concerns, FDA proposes to establish a dedicated Web page 
(or, alternatively, to modify an existing FDA Web page) on which FDA 
would promptly post information regarding the labeling changes proposed 
in a CBE-0 supplement while FDA is reviewing the supplement (see 
proposed Sec. Sec.  314.70(c)(8) and 601.12(f)(2)(iii)). The public may 
subscribe to FDA's free email subscription service to receive an email 
message each time there is an update to this proposed FDA Web page.
    The FDA Web page would provide information about pending CBE-0 
supplements for safety-related labeling changes, including but not 
limited to: The active ingredient, the trade name (if any), the 
application holder, the date on which the supplement was submitted, a 
description of the proposed labeling change and source of the 
information supporting the proposed labeling change (e.g., spontaneous 
adverse event reports, published literature, clinical trial, 
epidemiologic study), a link to the current labeling for the drug 
product containing the changes being effected, and the status of the 
pending CBE-0 supplement (e.g., whether FDA is reviewing the proposed 
labeling change, has taken an action on the CBE-0 supplement, or has 
determined that the supplement does not meet the criteria for a CBE-0 
supplement). It is expected that a valid safety concern regarding a 
generic drug product also would generally warrant submission of a 
supplement for a change to the labeling by the NDA holder for the RLD, 
as well as other ANDA holders. The CBE-0 supplements would remain 
posted on FDA's Web page until FDA has completed its review and issued 
an action letter. If the CBE-0 supplement is approved, the final 
approved labeling will be made available on the proposed FDA Web page 
through a link to FDA's online labeling repository at http://labels.fda.gov. After an adequate time period to communicate FDA's 
decision regarding approval of the CBE-0 labeling supplements and to 
facilitate submission of conforming CBE-0 supplements by other 
application holders, as appropriate, the original entry on FDA's Web 
page would be archived. Approved labeling would continue to be 
available at http://labels.fda.gov. As discussed in section II.B, a 
prior approval supplement or CBE-0 supplement submitted by an ANDA 
holder will be approved upon

[[Page 67990]]

the approval of the same safety-related labeling change for the RLD 
approved in an NDA under section 505(c) of the FD&C Act, except that if 
approval of the NDA for the RLD has been withdrawn under Sec.  314.150, 
FDA may approve an ANDA holder's prior approval supplement or CBE-0 
supplement (see section 505(j)(2)(A)(v) of the FD&C Act and proposed 
Sec.  314.97(b); see also section II.A.1.b and d). Upon FDA approval of 
revised labeling, other ANDA holders will be required to submit a CBE-0 
supplement with conforming revisions. We invite comment on this 
approach.
    Proposed Sec. Sec.  314.70(c)(8) and 601.12(f)(2)(iii) state that 
FDA will promptly post on its Web site information regarding labeling 
changes proposed in a CBE-0 supplement to an NDA, ANDA, or BLA. This 
proposal is intended to enhance transparency and facilitate access by 
health care providers and the public to labeling containing newly 
acquired information about important drug safety issues so that such 
information may be used to inform treatment decisions. We also invite 
comment on whether the benefits of a dedicated FDA Web page for CBE-0 
supplements could be realized through modification of FDA's existing 
online labeling repository (http://labels.fda.gov). For example, the 
online labeling repository could be modified to enable a separate 
listing of pending CBE-0 supplements, thereby improving existing 
resources and consolidating labeling information on a single FDA Web 
page.
    Current Sec. Sec.  314.70(c)(6) and 601.12(f)(2) state that the 
application holder may distribute the drug accompanied by the revised 
labeling upon submission to FDA of a CBE-0 supplement. However, FDA 
expects that if an application holder acquires important new safety-
related information that warrants submission of a CBE-0 supplement 
under Sec. Sec.  314.70(c)(6) or 601.12(f)(2), the application holder 
will use available means (e.g., distribution of revised labeling in 
electronic format to the public) to distribute the revised labeling at 
the time of submission of the CBE-0 supplement to FDA (compare section 
II.A.1.d). Indeed, the need to promptly communicate certain safety-
related labeling changes based on newly acquired information is the 
basis for this exception to the general requirement for FDA approval of 
revised labeling prior to distribution (see section I.B). Accordingly, 
we are proposing to expressly require that applicants submit final 
printed labeling in structured product labeling (SPL) format at the 
time of submission of the CBE-0 supplement so that the revised labeling 
can be made publicly available on FDA's Web site and in other databases 
(e.g., DailyMed, a Web site provided by the National Library of 
Medicine that includes drug labeling submitted to FDA) promptly after 
submission. This proposed change would make the regulations consistent 
with FDA's previous announcement that ``the Agency will make the 
revised labeling proposed in a CBE supplement publicly available on its 
Web site and through the DailyMed shortly after the CBE supplement is 
received and before FDA has necessarily reviewed or approved it'' 
(draft guidance for industry on ``Public Availability of Labeling 
Changes in 'Changes Being Effected' Supplements'' (2006)).\2\ We note 
that the technical means by which the CBE-0 supplements are made 
publicly available through the FDA Web site may change with evolving 
technology and Agency practices.
---------------------------------------------------------------------------

    \2\ When final, this guidance will represent FDA's current 
thinking on this topic. For the most recent version of a guidance, 
check the FDA Drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
---------------------------------------------------------------------------

    Proposed Sec. Sec.  314.70(c)(8) and 601.12(f)(2)(iii) would 
require the applicant to verify that the correct information regarding 
the labeling changes proposed in its CBE-0 supplement appears on FDA's 
Web page. If the information is incorrect, then the applicant must 
contact FDA within 5 business days of posting on the FDA Web page. The 
applicant may determine that information regarding the labeling changes 
proposed in its CBE-0 supplement has been posted on the FDA Web page by 
monitoring the FDA Web page after submission of a CBE-0 supplement or 
subscribing to FDA's Web page to receive an email notification. FDA 
intends to identify the FDA contact person(s) who should receive any 
corrections to such information for NDAs, ANDAs, and BLAs on the 
proposed FDA Web page. We invite comment on whether this is a 
sufficient amount of time for an applicant to check the accuracy and 
completeness of the posted information regarding the CBE-0 supplement 
and the link to current labeling.
    a. Contents of supplement. We are proposing to add Sec.  
314.70(c)(8)(i) to clarify FDA's expectations regarding the contents of 
a CBE-0 supplement submitted under Sec.  314.70(c)(6)(iii), and to 
facilitate publication of information regarding the CBE-0 supplement on 
FDA's Web page. Current Sec.  314.70(c)(4) requires that a CBE 
supplement include information listed in Sec.  314.70(b)(3)(i) through 
(b)(3)(vii), which describes information that must be included in a CBE 
supplement for a manufacturing change. To clarify FDA's expectations 
for the contents of a CBE-0 labeling supplement and to facilitate 
listing information on FDA's proposed Web page, we are proposing to 
require that a CBE-0 supplement submitted under Sec.  314.70(c)(6)(iii) 
contain the following information:
    i. The application number(s) of the drug product(s) involved. If a 
CBE-0 supplement is being submitted by an NDA or ANDA holder to 
multiple applications for a drug product or product class, the 
application holder should identify the application number of each 
application to which the CBE-0 supplement is being submitted.
    ii. A description of the labeling change proposed in the CBE-0 
supplement. The applicant should submit a proposed narrative 
description of the proposed labeling change in the CBE-0 supplement for 
posting on the FDA Web page. This brief narrative description should 
include the affected section(s) of labeling, the labeling change, and 
the source of the data (e.g., spontaneous adverse event reports, 
published literature, clinical trial, epidemiologic study). For 
example, ``Revised contraindication: Drug X is contraindicated in 
patients with diabetes. Source: Published literature, epidemiologic 
study.''
    iii. The basis for the labeling change proposed in the CBE-0 
supplement. The basis for the labeling change proposed in the CBE-0 
supplement should include available data supporting the change (e.g., 
spontaneous adverse event reports, published literature, clinical 
trial, epidemiologic study). If the supplement has been submitted in 
response to FDA's specific request to submit a CBE-0 supplement for the 
labeling change (see Sec.  314.70(c)(6)(iii)(E)), the applicant should 
describe the specific change requested by FDA and reference the FDA 
communication containing the request.
    iv. A copy of the product labeling proposed in the CBE-0 
supplement. A copy of the final printed labeling containing the changes 
being effected should be provided in SPL format for posting on FDA's 
Web site and distribution to DailyMed. The application holder also 
should submit a copy of the current product labeling annotated with the 
labeling change proposed in the CBE-0 supplement (e.g., use of 
underscoring and/or strikethrough text to show the changes being 
effected in the product labeling

[[Page 67991]]

proposed in the CBE-0 supplement as compared to the approved labeling).
    v. Confirmation that notice has been sent to the NDA holder for the 
RLD. If the changes being effected supplement is submitted by an ANDA 
holder and approval of the NDA for the RLD has not been withdrawn under 
Sec.  314.150, the ANDA holder must include in its submission a 
statement confirming that the notice described in proposed Sec.  
314.70(c)(8)(ii) has been sent to the NDA holder for the RLD.
    b. Notice of labeling changes being effected. We are proposing to 
add Sec.  314.70(c)(8)(ii) to require an ANDA holder to send notice of 
the labeling change proposed in the CBE-0 supplement, including a copy 
of the information supporting the change (with any personally 
identifiable information redacted), to the NDA holder for the RLD at 
the same time that the supplement to the ANDA is submitted to FDA, 
unless approval of the NDA has been withdrawn under Sec.  314.150. This 
proposal would ensure that the NDA holder for the RLD is promptly 
advised of the newly acquired information that was considered to 
warrant the labeling change proposed for the drug in the CBE-0 
supplement.
    The ANDA holder would be required to send a copy of the information 
(e.g., published literature, spontaneous adverse event reports) 
supporting the labeling change described in the CBE-0 supplement to the 
NDA holder for the RLD so that the NDA holder may consider this 
information as part of its review and evaluation of postmarketing data 
under Sec.  314.80(b). If the information supporting the ANDA holder's 
labeling change described in the CBE-0 supplement contains personally 
identifiable information (e.g., spontaneous adverse event reports), the 
ANDA holder should redact that information prior to sending a copy of 
the information to the NDA holder for the RLD, in accordance with 21 
CFR 20.63(f). The NDA holder has full access to the data upon which the 
RLD was approved and, in most cases, has substantial knowledge about 
the postmarketing experience for the drug product. FDA's analysis of 
whether the labeling change proposed by an ANDA holder in a CBE-0 
supplement should be approved (and required for inclusion in the 
labeling of all versions of the drug) would benefit from the views of 
the NDA holder for the listed drug that was the basis for ANDA 
submission. Other holders of NDAs or ANDAs for drug products containing 
the same active ingredient may learn of pending CBE-0 supplements by 
subscribing to FDA's proposed Web page, and also may submit CBE-0 
supplements or provide comments to FDA regarding a pending CBE-0 
supplement. This approach to considering information from other 
application holders is intended to mitigate concerns that a single ANDA 
holder may not possess sufficient data to perform an adequate 
assessment of the potential new safety concern raised by the newly 
acquired information.
    It should be emphasized that interpretation of postmarketing safety 
data is complex, involving analysis of postapproval clinical data, 
detailed review of adverse drug experience reports in the context of 
relevant clinical studies, estimates of drug usage and adverse drug 
experience reporting rates, estimates of background rates of the 
adverse event, and other relevant information. FDA recognizes that 
decisions about how to address a safety concern often are a matter of 
judgment, about which reasonable persons with relevant expertise may 
disagree, and this may be reflected in different approaches to proposed 
labeling changes based on newly acquired safety information (see 
Guidance on ``Drug Safety Information--FDA's Communication to the 
Public'' (2007)). Figure 1 illustrates one of the possible scenarios 
involving submission of CBE-0 supplements by multiple application 
holders.
BILLING CODE 4160-01-P

[[Page 67992]]

[GRAPHIC] [TIFF OMITTED] TP13NO13.029

BILLING CODE 4160-01-C
    Proposed Sec.  314.70(c)(8)(ii) would provide that an NDA holder or 
any ANDA holder may submit (on its own initiative or in response to a 
request from FDA) a labeling supplement or correspondence to its NDA or 
ANDA, as applicable, regarding the labeling changes proposed in a CBE-0 
supplement. It is expected that a valid safety concern regarding a 
generic drug product also would generally warrant a change to the 
labeling through a CBE-0 supplement by the NDA holder for the RLD and, 
as a consequence, other generic drug products that reference the RLD. 
In the event that the NDA holder for the RLD does not submit a 
supplement seeking approval for a related or conforming labeling 
change, FDA may send a supplement request letter to the NDA holder or, 
if appropriate, notify the responsible person of new safety information 
under section 505(o)(4) of the FD&C Act (see 21 U.S.C. 355(o)(2)(A) 
defining ``responsible person''). In situations in which the safety 
information prompting the submission of the CBE-0 supplement would 
require a label change for other drugs containing the same active 
ingredient, even if approved under a different NDA, FDA also may send a 
supplement request letter to the persons responsible for those other 
drugs.
    We recognize that the authority to order safety labeling changes 
under section 505(o)(4) of the FD&C Act for new safety information 
about a risk of a serious adverse drug experience will not apply to all 
potential safety-related labeling changes (see 21 U.S.C. 355-1(b) 
defining ``new safety information'' and ``serious adverse drug 
experience''). Based on our experience, we expect that NDA holders will 
implement safety-related labeling changes requested by FDA even if not 
required under section 505(o)(4) of the FD&C Act. In circumstances in 
which section 505(o)(4) of the FD&C Act does not apply, if the NDA 
holder declined to submit a supplement to make the

[[Page 67993]]

change that FDA has concluded is appropriate, FDA would consider 
whether the NDA holder's failure to update its labeling would warrant 
the initiation of proceedings to withdraw approval of the NDA (see 
section 505(e) of the FD&C Act).
    It should be noted that if an NDA holder has discontinued marketing 
a drug product, but approval of the NDA has not been withdrawn under 
Sec.  314.150, the NDA holder still must comply with applicable 
statutory and regulatory requirements. These requirements include, for 
example, postmarketing reporting of adverse drug experiences, 
submission of an annual report (including a brief summary of 
significant new information from the previous year that might affect 
the safety, effectiveness, or labeling of the drug product, and a 
description of actions the applicant has taken or intends to take as a 
result of this new information) and, if appropriate, proposed revisions 
to product labeling. If approval of the NDA for the RLD is withdrawn 
under Sec.  314.150 for reasons other than safety or effectiveness, any 
generic versions that remain on the market will be expected to contain 
the same essential labeling.
    c. Distribution of revised labeling. We are proposing to add Sec.  
314.70(c)(8)(iii) and revise Sec.  601.12(f)(2)(ii) to expressly 
describe our longstanding practice with respect to labeling supplements 
that have been submitted as CBE-0 supplements, but that do not meet the 
regulatory criteria for CBE-0 supplements, and thus do not fall within 
this narrow exception to the general requirement for FDA approval of 
revised labeling prior to distribution. Proposed Sec. Sec.  
314.70(c)(8)(iii) and 601.12(f)(2)(ii) explain that if FDA determines 
during its review period that the supplement does not meet the criteria 
described in Sec.  314.70(c)(6)(iii) or Sec.  601.12(f)(2)(i), as 
applicable, the supplement will be converted to a prior approval 
supplement, and the manufacturer must cease distribution of the drug 
product(s) accompanied by the revised labeling. In this scenario, the 
manufacturer must take steps to make the drug product available only 
with the previous version of the label. This may include, for example, 
replacing the CBE-0 labeling with the previous labeling on the 
manufacturer's Web site, requesting replacement of the CBE-0 labeling 
with the previous labeling on http://labels.fda.gov, and attaching the 
previous package insert to the drug product as soon as feasible 
thereafter or at the time of next printing of the product labeling for 
packaging.
    This approach is consistent with our clarifying revision in 
proposed Sec.  314.70(c)(7), which explains that if the Agency does not 
approve the supplemental application, the manufacturer must cease 
distribution of the drug product(s) accompanied by the revised 
labeling. The current text of Sec.  314.70(c)(7) describes the 
implications of a complete response letter to the applicant for a CBE 
supplement for manufacturing changes, and does not expressly address 
CBE-0 labeling supplements. For consistency with Sec.  314.110 (21 CFR 
314.110), we are proposing to replace the word ``disapproves'' in Sec.  
314.70(c)(7) with the phrase ``issues a complete response letter'' and 
to make other editorial changes for clarity.
    d. Conforming labeling requirements. Proposed Sec.  
314.70(c)(8)(iv) would establish a 30-day timeframe in which ANDA 
holders are required to submit a CBE-0 supplement under Sec.  
314.70(c)(6)(iii)(E) with conforming labeling after FDA approval of a 
revision to the labeling for the RLD. Currently, FDA advises ANDA 
holders to revise product labeling to conform to the labeling of the 
RLD ``at the very earliest time possible'' (see guidance for industry 
on ``Revising ANDA Labeling Following Revision of the RLD Labeling'' 
(2000)). In light of the range of timeframes in which ANDA holders 
currently submit such labeling supplements, we are proposing to revise 
these regulations to clarify FDA's expectations regarding the timeframe 
for submission of conforming labeling changes.
    Proposed Sec.  314.70(c)(8)(iv) states that upon FDA approval of 
changes to the labeling of the RLD, or if approval of the NDA for the 
RLD has been withdrawn under Sec.  314.150, upon FDA approval of 
changes to the labeling of an ANDA that relied on the RLD, any other 
ANDA holder that relied upon the RLD must submit a CBE-0 supplement 
with conforming labeling revisions within 30 days of FDA's posting of 
the approval letter for the labeling change on FDA's Web site, unless 
FDA requires the ANDA holder's labeling revisions at a different time 
in accordance with sections 505(o)(4) or 505-1 of the FD&C Act, or 
other applicable authority. The ANDA holder would be expected to submit 
updated labeling for posting on http://labels.fda.gov and DailyMed at 
the time of submission of the CBE-0 supplement. However, we recognize 
that distribution of drug products accompanied by an updated package 
insert may take additional time, depending on how often the drug is 
packaged, the size of manufacturer inventories, and other factors. 
Accordingly, proposed Sec.  314.70(c)(8)(iv) is directed to prompt 
distribution of revised labeling in electronic format, and timely 
distribution of drug product accompanied by an updated package insert 
as soon as feasible thereafter or at the time of next printing of the 
product labeling for packaging.
    FDA may require an ANDA holder to submit revised product labeling 
at a different time for safety labeling changes required under section 
505(o)(4) of the FD&C Act or for REMS under section 505-1 of the FD&C 
Act. This may occur, for example, in the context of approval of 
modifications to a single, shared system REMS that are made to conform 
to safety labeling changes (see section 505-1(i)(1)(B) of the FD&C 
Act).
2. Changes to Highlights of Prescribing Information (Proposed 
Sec. Sec.  314.70(c)(6) and 601.12(f)(1) and (f)(2))
    We are proposing to revise Sec. Sec.  314.70(c)(6) and 601.12(f)(1) 
and (f)(2) to remove the limitation on submission of CBE-0 supplements 
for changes to the Highlights of drug labeling in the PLR format.
    Current Sec. Sec.  314.70(c)(6) and 601.12(f)(1) and (f)(2) exclude 
most changes to the information required in the Highlights, which are 
classified as a ``major change'' that must be made by a prior approval 
supplement, unless FDA specifically requests that the labeling change 
be submitted in a CBE-0 supplement or FDA grants a waiver request under 
Sec.  314.90. This exception reflected the Agency's earlier view that 
FDA review and approval of most proposed changes to the information in 
the Highlights of labeling was necessary because of the difficulty 
involved in summarizing the complex information presented in the full 
prescribing information (see ``Requirements on Content and Format of 
Labeling for Human Prescription Drug and Biological Products,'' 71 FR 
3922 at 3932, January 24, 2006).
    Based on our experience implementing the PLR, we have found this 
restriction on CBE-0 supplements to be unnecessary in practice. In 
response to an applicant's inquiry about submission of a CBE-0 
supplement for a change that would affect the Highlights of drug 
labeling, FDA typically waives this limitation under Sec.  314.90 or 
specifically requests that the applicant proceed with a CBE-0 
supplement under Sec.  314.70(c)(6)(iii)(E) or Sec.  
601.12(f)(2)(i)(E).
    The Highlights of drug labeling is intended to summarize the 
information that is most important for prescribing the drug safely and 
effectively. The

[[Page 67994]]

types of newly acquired information that would otherwise meet the 
criteria for submission of a CBE-0 supplement include the critical 
safety information that is presented in the Highlights. Accordingly, we 
believe that limiting the availability of CBE-0 supplements for changes 
to the Highlights of drug labeling in the PLR format may pose an 
unnecessary impediment to prompt communication of the most important 
safety-related labeling changes (e.g., boxed warnings and 
contraindications). Compare 50 FR 7452 at 7470, February 22, 1985 
(stating that substantive changes in labeling are appropriately 
approved by FDA in advance, ``unless they relate to important safety 
information, like a new contraindication or warning, that should be 
immediately conveyed to the user'').
    Our proposal to remove the limitation on submission of CBE-0 
supplements for changes to the Highlights also would create parity 
between application holders for drugs with labeling in the older format 
and application holders for drugs with PLR labeling. For example, this 
proposal would eliminate differences in the ability of application 
holders to submit CBE-0 supplements for a new or substantively revised 
contraindication based solely on whether current labeling appeared in 
the older format or PLR format.
    We also are proposing to make conforming revisions to Sec.  
314.70(b)(2)(v)(C) to clarify that a prior approval supplement is 
required for any changes to the Highlights of drug labeling other than 
changes under Sec.  314.70(c)(6)(iii), except for the specified changes 
that may be reported in an annual report.
3. Clarifying Revisions and Editorial Changes
    We are proposing to revise the title to Sec.  314.70(c) to refer to 
CBE-0 supplements to clarify the scope of paragraph (c). As revised, 
Sec.  314.70(c) would describe changes requiring supplement submission 
at least 30 days prior to distribution of the drug product made using 
the change (CBE-30 supplements) and certain changes being effected 
pending supplement approval (CBE-0 supplements). We also are proposing 
to add titles to paragraphs (c)(1) through (c)(7) of Sec.  314.70 for 
clarity.
    We are proposing to revise Sec.  314.70(c)(1) to clarify that 
submission of a CBE-0 supplement is required for any change in the 
labeling to reflect newly acquired information of the type described in 
Sec.  314.70(c)(6)(iii). The current text of Sec.  314.70(c)(1) is 
directed only to submission of supplements for certain manufacturing 
changes and does not fully describe the range of supplements for 
moderate changes that are described by this paragraph.
    We are proposing to move the statement regarding the contents of a 
CBE supplement for certain manufacturing changes from existing Sec.  
314.70(c)(4) to Sec.  314.70(c)(3) without changes.
    We are proposing to revise Sec.  314.70(c)(6)(iii) to clarify that 
an NDA holder or ANDA holder may distribute the drug product with 
revised labeling upon ``submission'' to FDA of the CBE-0 supplement for 
the labeling change, rather than upon FDA's ``receipt'' of the change. 
For ANDAs, section 744B(a)(5) of the FD&C Act (21 U.S.C. 379j-42(a)(5)) 
clarifies the time when a supplement is ``submitted'' to FDA, whereas 
the term ``received'' has a specific meaning that generally refers to 
FDA's determination that a submitted application has met certain 
criteria for completeness (see 21 CFR 314.101). This proposed revision 
is intended to avoid potential confusion, and more clearly establish 
the date on which distribution of revised labeling may occur.

B. Approval of Supplements to an Approved ANDA for a Labeling Change 
(Proposed Sec.  314.97(b))

    We are proposing to revise Sec.  314.97 by designating the current 
text as paragraph (a) and by adding proposed paragraph (b) to clarify 
the process for approval of a supplement to an approved ANDA for a 
labeling change. Proposed Sec.  314.97(b) explains that a supplement to 
an approved ANDA for a safety-related labeling change that is submitted 
in a prior approval supplement under Sec.  314.70(b) or in a CBE-0 
supplement under Sec.  314.70(c)(6) will be approved upon approval of 
the same labeling change for the RLD, except that if approval of the 
NDA for the RLD has been withdrawn under Sec.  314.150, FDA may approve 
an ANDA holder's prior approval supplement or CBE-0 supplement.
    It has been FDA's longstanding position that an ANDA holder may 
submit a prior approval supplement to request a change to product 
labeling, and ``FDA will determine whether the labeling for the generic 
and [reference] listed drugs should be revised'' (57 FR 17950 at 17961, 
April 28, 1992; see also 57 FR 17950 at 17965 (describing requirement 
for ``ANDA applicants to submit a periodic report of adverse drug 
experiences even if the ANDA applicant has not received any adverse 
drug experience reports or initiated any labeling changes'') (emphasis 
added)). Proposed Sec.  314.97(b) would expressly state that a prior 
approval supplement to an ANDA for a safety-related change in product 
labeling will be approved upon approval of the same labeling for the 
RLD. This approach ensures that the approved labeling for a generic 
drug continues to be the same as the approved labeling of its RLD (see 
section 505(j)(2)(A)(v) of the FD&C Act). If approval of the NDA for 
the RLD has been withdrawn under Sec.  314.150, FDA may approve an ANDA 
holder's prior approval supplement for a safety-related labeling change 
(see Sec.  314.105; see also proposed Sec.  314.70(c)(8)(iv)).
    Similarly, FDA would approve a CBE-0 labeling supplement to an ANDA 
upon the approval of the same labeling change for the RLD (see section 
505(j)(2)(A)(v) of the FD&C Act), except that if approval of the NDA 
for the RLD has been withdrawn under Sec.  314.150, FDA may approve an 
ANDA holder's CBE-0 supplement (see Sec.  314.105; see also proposed 
Sec.  314.70(c)(8)(iv)). As explained in section I.B, FDA may accept, 
reject, or request modifications to the labeling changes proposed in 
the CBE-0 supplement. FDA's evaluation of the labeling change proposed 
by the ANDA holder would consider any submissions related to the 
proposed labeling change from the NDA holder for the RLD and from any 
other NDA or ANDA holders for drug products containing the same active 
ingredient. The Agency intends to act expeditiously, taking into 
account the reliability of the data, the magnitude and seriousness of 
the risk, and number of CBE-0 supplements, and reach a decision on the 
approvability of labeling proposed by ANDA and NDA holders regarding 
the safety issue at the same time. After approval of a labeling change, 
other ANDA holders would be required to submit any necessary conforming 
labeling changes in accordance with proposed Sec.  314.70(c)(8)(iv).

C. Exception for ANDA Labeling Differences Resulting From ``Changes 
Being Effected'' Supplement (Proposed Sec.  314.150(b)(10)(iii))

    We are proposing to revise Sec.  314.150(b)(10) to provide an 
additional exception regarding circumstances in which FDA may seek to 
withdraw approval of an ANDA based on generic drug labeling that is no 
longer consistent with the labeling for the RLD. Proposed Sec.  
314.150(b)(10)(iii) would include, as a permissible difference, changes 
to generic drug labeling under a CBE-0 supplement, with the 
understanding that such differences generally will be temporary.

[[Page 67995]]

    This proposed exception reflects the Agency's judgment that 
concerns related to temporary differences in labeling between generic 
drugs and their RLDs are outweighed by the benefit to the public health 
that would result from all application holders having the ability to 
independently update drug product labeling to reflect newly acquired 
information regarding important drug safety issues through CBE-0 
labeling supplements (compare section 505(j)(10) of the FD&C Act).

III. Legal Authority

    FDA's legal authority to modify Sec. Sec.  314.70, 314.97, 314.150, 
and 601.12 arises from the same authority under which FDA initially 
issued these regulations. The FD&C Act (21 U.S.C. 301 et seq.) and the 
PHS Act (42 U.S.C. 201 et seq.) provide FDA with authority over the 
labeling for drugs and biological products, and authorize the Agency to 
enact regulations to facilitate FDA's review and approval of 
applications regarding the labeling for those products. Section 502 of 
the FD&C Act (21 U.S.C. 352) provides that a drug or biological product 
will be considered misbranded if, among other things, the labeling for 
the product is false or misleading in any particular (21 U.S.C. 352(a); 
see also 42 U.S.C. 262(j)). Under section 502(f) of the FD&C Act, a 
product is misbranded unless its labeling bears adequate directions for 
use, including adequate warnings against, among other things, unsafe 
dosage or methods or duration of administration or application. 
Moreover, under section 502(j) of the FD&C Act, a product is misbranded 
if it is dangerous to health when used in the manner prescribed, 
recommended, or suggested in its labeling.
    In addition to the misbranding provisions, the premarket approval 
provisions of the FD&C Act authorize FDA to require that product 
labeling provide adequate information to permit safe and effective use 
of the product. Under section 505(c) of the FD&C Act (21 U.S.C. 355), 
FDA will approve an NDA only if the drug is shown to be both safe and 
effective for its intended use under the conditions set forth in the 
drug's labeling. Under section 505(j) of the FD&C Act, FDA will approve 
an ANDA only if the drug is, with limited exceptions, the same as a 
drug previously approved under section 505(c) of the FD&C Act with 
respect to active ingredient(s), dosage form, route of administration, 
strength, labeling, and conditions of use, among other characteristics, 
and is bioequivalent to the RLD.
    Section 351 of the PHS Act (42 U.S.C. 262) provides additional 
legal authority for the Agency to regulate the labeling of biological 
products. Licenses for biological products are to be issued only upon a 
showing that the biological product is safe, pure, and potent (42 
U.S.C. 262(a)). Section 351(b) of the PHS Act prohibits any person from 
falsely labeling any package or container of a biological product. 
FDA's regulations in 21 CFR part 201 apply to all prescription drug 
products, including biological products.
    In addition, section 701(a) of the FD&C Act (21 U.S.C. 371(a)) 
authorizes FDA to issue regulations for the efficient enforcement of 
the FD&C Act. FDA's regulations relating to CBE-0 supplements are 
supported by this provision. In 1965, FDA determined that, in the 
interest of drug safety, manufacturers should make certain safety-
related changes to their product labeling at the earliest possible time 
(see 30 FR 993, January 30, 1965). Thus, for nearly 50 years, FDA, as 
the Agency entrusted with administration and enforcement of the FD&C 
Act and the protection and promotion of the public health, has required 
NDA holders, and subsequently BLA holders, to update drug product 
labeling with important, newly acquired safety information through 
submission of a CBE-0 supplement.
    FDA's authority to extend the CBE-0 supplement process for safety-
related labeling changes to ANDA holders arises from the same authority 
under which our regulations relating to NDA holders and BLA holders 
were issued. Nothing in the Hatch-Waxman Amendments or subsequent 
amendments to the FD&C Act limits the Agency's authority to revise the 
CBE-0 supplement regulations to apply to ANDA holders to help ensure 
that generic drugs remain safe and effective under the conditions of 
use prescribed, recommended, or suggested in the labeling throughout 
the life cycle of the generic drug product.
    In Pliva v. Mensing, the Supreme Court recognized that ``Congress 
and the FDA retain the authority to change the law and regulations if 
they so desire'' (131 S. Ct. 2567, 2582). Recently, in Mutual 
Pharmaceutical Co., Inc. v. Bartlett, 133 S. Ct. 2466 (2013), the Court 
indicated that ``Congress' decision to regulate the manufacture and 
sale of generic drugs in a way that reduces their cost to patients but 
leaves generic drug manufacturers incapable of modifying either the 
drugs' compositions or their warnings'' contributed to the outcome in 
that case (preemption of the tort claim against the generic 
manufacturer). We do not read this language to suggest that the Agency 
would not have authority to extend the CBE-0 supplement process to ANDA 
holders. The changes proposed in this rulemaking are authorized under 
the FD&C Act, which provides authority for FDA to permit NDA holders 
and BLA holders to change their product labeling to include certain 
newly acquired safety-related information through submission of a CBE-0 
supplement.

IV. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. 
L.104-4). Executive Orders 12866 and 13563 direct Agencies to assess 
all costs and benefits of available regulatory alternatives and, when 
regulation is necessary, to select regulatory approaches that maximize 
net benefits (including potential economic, environmental, public 
health and safety, and other advantages; distributive impacts; and 
equity). The Agency believes that this proposed rule would not be an 
economically significant regulatory action as defined by Executive 
Order 12866.
    If a rule has a significant economic impact on a substantial number 
of small businesses, the Regulatory Flexibility Act requires Agencies 
to analyze regulatory alternatives that would minimize any significant 
impact of a rule on small entities. FDA has determined that this 
proposed rule would not have a significant economic impact on a 
substantial number of small entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that Agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $141 million, using the most current (2012) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
proposed rule to result in any 1-year expenditure that would meet or 
exceed this amount.
    The public health benefits from adoption of the proposed rule are 
not quantified. By allowing all application holders to update labeling 
based on newly acquired information that meets

[[Page 67996]]

the criteria for a CBE-0 supplement, communication of important drug 
safety information to prescribing health care providers and the public 
could be improved. The proposed rule may reduce the time in which ANDA 
holders make safety-related labeling changes for generic drugs for 
which approval of the NDA for the RLD has been withdrawn. In addition, 
the proposed rule generally would reduce the time in which all ANDA 
holders make safety-related labeling changes, by requiring such ANDA 
holders to submit conforming labeling changes within 30 days of FDA's 
posting of the approval letter for the RLD's labeling change on its Web 
site. The primary estimate of the costs of the proposed rule includes 
costs to ANDA and NDA holders for submitting and reviewing CBE-0 
supplements. We assume that the proposed rule will have no effect on 
the number of CBE-0 supplements submitted by BLA holders.
    The proposed rule is expected to generate little cost. The Agency 
estimates the net annual social costs to be between $4,237 and $25,852. 
The present discounted value over 20 years would be in the range of 
$63,040 to $384,616 at a 3 percent discount rate, and in the range of 
$44,890 to $273,879 at a 7 percent discount rate.
    FDA has examined the economic implications of the final rule as 
required by the Regulatory Flexibility Act. This proposed rule would 
only impose new burdens on small generic drug manufacturers who submit 
CBE-0 supplements for safety-related labeling changes. Given the small 
cost per submission and the uncertainty in the estimated number of CBE-
0 labeling supplements for safety-related labeling changes that may be 
submitted by an ANDA holder, we do not expect this proposed rule to 
impose a significant impact on a substantial number of small entities. 
We therefore propose to certify that that this proposed rule would not 
have a significant economic impact on a substantial number of small 
entities.

V. Paperwork Reduction Act of 1995

    This proposed rule contains collections of information that are 
subject to review by the Office of Management and Budget (OMB) under 
the PRA (44 U.S.C. 3501-3520). A description of these provisions is 
given in this document with an estimate of the annual reporting burden. 
Included in the estimate is the time for reviewing instructions, 
searching existing data sources, gathering and maintaining the data 
needed, and completing and reviewing the collection of information.
    FDA invites comments on these topics: (1) Whether the proposed 
collection of information is necessary for the proper performance of 
FDA's functions, including whether the information will have practical 
utility; (2) the accuracy of FDA's estimate of the burden of the 
proposed collection of information, including the validity of the 
methodology and assumptions used; (3) ways to enhance the quality, 
utility, and clarity of the information to be collected; and (4) ways 
to minimize the burden of the collection of information on respondents, 
including through the use of automated collection techniques, when 
appropriate, and other forms of information technology.
    Title: Supplemental Applications Proposing Labeling Changes for 
Approved Drugs and Biological Products
    Description: The proposed rule would permit ANDA holders to submit 
a CBE-0 supplement for certain types of labeling changes based on newly 
acquired information. At the time of submission, the ANDA holder would 
be required to send notice of the labeling change proposed in the CBE-0 
supplement, including a copy of the information supporting the change, 
to the NDA holder for the RLD, unless the NDA for the RLD has been 
withdrawn.
    Description of Respondents: Respondents to this collection of 
information are NDA holders, ANDA holders, and BLA holders.
    Burden Estimates: FDA regulations at Sec. Sec.  314.70 and 314.97 
set forth the requirements for submitting supplements to FDA for 
certain changes to an approved NDA or ANDA. These regulations specify 
the submission of supplements at different times, depending on the 
change to the approved application. Under Sec.  314.70(c)(6), an 
applicant may commence distribution of a drug product upon receipt by 
FDA of a supplement for a change to the applicant's approved 
application (a CBE-0 supplement). The changes for which a CBE-0 
supplement may be submitted include, among other things, changes in the 
labeling (Sec.  314.70(c)(6)(iii)) to reflect newly acquired 
information, for example, to add or strengthen a contraindication, 
warning, precaution, or adverse reaction for which there is reasonable 
evidence of a causal association.
    FDA currently has OMB approval (OMB control number 0910-0001) for 
the submission of supplements to FDA for changes to an approved NDA or 
ANDA under Sec. Sec.  314.70 (including Sec.  314.70(c)(6)(iii)) and 
314.97.
    Under the proposed rule, ANDA holders would be permitted to submit 
a supplement to FDA for certain types of labeling changes based on 
newly acquired information. This collection of information is not 
currently approved under OMB control number 0910-0001. Under proposed 
Sec.  314.70(c)(8), if an NDA holder or ANDA holder obtains or 
otherwise receives newly acquired information that should be reflected 
in product labeling to accomplish any of the objectives specifically 
described in Sec.  314.70(c)(6)(iii), the NDA holder or ANDA holder 
should submit a CBE-0 supplement to FDA. Proposed Sec.  314.70(c)(8) is 
intended to permit ANDA holders to update product labeling promptly, 
without FDA's special permission and assistance, to reflect newly 
acquired information that meets the criteria described in Sec.  
314.70(c)(6)(iii) irrespective of whether the revised labeling differs 
from that of the RLD.
    To minimize confusion and make safety-related changes to generic 
drug labeling readily available to prescribing health care providers 
and the public while FDA is reviewing a CBE-0 supplement, FDA would 
establish, under proposed Sec.  314.70(c)(8), a dedicated Web page (or, 
alternatively, a modification of an existing FDA Web page) on which FDA 
would promptly post information regarding the labeling changes proposed 
in a CBE-0 supplement. ANDA holders would be required to verify that 
the correct information regarding the labeling changes proposed in 
their CBE-0 supplement appears on the FDA Web page. If the information 
is incorrect, the ANDA holder must contact the appropriate FDA review 
division within 2 business days of posting on the FDA Web page.
    At the time of submission of the CBE-0 labeling supplement to FDA, 
proposed Sec.  314.70(c)(8)(ii) would require the ANDA holder to send 
notice of the labeling change proposed in the supplement, including a 
copy of the information supporting the change, to the NDA holder for 
the RLD, unless the NDA for the RLD has been withdrawn.
    Based on the data summarized in section IV (Analysis of Impacts), 
we estimate that a total of approximately 15 ANDA holders (``number of 
respondents'' in table 1) would submit to us annually a total of 
approximately 20 CBE-0 labeling supplements under proposed Sec.  
314.70(c)(8), if this rule is finalized (``total annual responses'' in 
table 1). We also estimate that preparing and submitting each CBE-0 
labeling supplement under proposed Sec.  314.70(c)(8) will take 
approximately 12 hours per ANDA holder (``hours per response'' in table 
1). This burden hour estimate includes the time needed by an

[[Page 67997]]

ANDA holder to verify, as required under proposed Sec.  314.70(c)(8), 
that the correct information regarding the labeling change proposed in 
its CBE-0 supplement appears on the FDA Web page, and the time needed 
to contact FDA if the information is incorrect.
    In addition, we estimate that a total of approximately 15 ANDA 
holders would send notice of the labeling change proposed in each of 
the 20 CBE-0 labeling supplements, including a copy of the information 
supporting the change, to the NDA holder for the RLD, as required under 
proposed Sec.  314.70(c)(8)(ii). We also estimate that preparing and 
sending each notice would take approximately 3 hours per ANDA holder.
    FDA estimates the burden of this collection of information as 
follows:

                                 Table 1--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                     Number of
         21 CFR Section              Number of     responses per   Total annual      Hours per      Total hours
                                    respondents     respondent       responses       response
----------------------------------------------------------------------------------------------------------------
CBE-0 supplement submission by                15            1.34              20              12             240
 ANDA holders (314.70(c)(8))....
ANDA holder notice to NDA holder              15            1.34              20               3              60
 (314.70(c)(8)(ii)).............
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............  ..............  ..............             300
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

    To ensure that comments on the information collection are received, 
OMB recommends that written comments be faxed to the Office of 
Information and Regulatory Affairs, OMB, Attn: FDA Desk Officer, FAX: 
202-395-7245, or emailed to [email protected]. All comments 
should be identified with the title, ``Supplemental Applications 
Proposing Labeling Changes for Approved Drugs and Biological 
Products.''
    In compliance with the PRA (44 U.S.C. 3407(d)), the Agency has 
submitted the information collection provisions of this proposed rule 
to OMB for review. These requirements will not be effective until FDA 
obtains OMB approval. FDA will publish a notice concerning OMB approval 
of these requirements in the Federal Register.

VI. Environmental Impact

    The Agency has determined under 21 CFR 25.30(h) and 25.31(a) and 
(g) that this action is of a type that does not individually or 
cumulatively have a significant effect on the human environment. 
Therefore, neither an environmental assessment nor an environmental 
impact statement is required.

VII. Effective Date

    FDA proposes that any final rule based on this proposal become 
effective 30 days after the date of its publication in the Federal 
Register.
    We intend to apply this rule, if finalized, to any submission 
received by FDA on or after the effective date. This proposed rule 
provides sufficient notice to all interested parties, including NDA 
holders, ANDA holders, and BLA holders, to adjust their submissions and 
actions by the time we issue any final rule. However, we invite 
comments on how a final rule should be implemented.

VIII. Federalism

    FDA has analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the proposed rule, if finalized, would not contain policies that would 
have substantial direct effects on the States, on the relationship 
between the National Government and the States, or on the distribution 
of power and responsibilities among the various levels of government. 
Accordingly, the Agency tentatively concludes that the proposed rule 
does not contain policies that have federalism implications as defined 
in the Executive order and, consequently, a federalism summary impact 
statement is not required.

IX. Request for Comments

    Interested persons may submit either electronic comments regarding 
this document to http://www.regulations.gov or written comments to the 
Division of Dockets Management (see ADDRESSES). It is only necessary to 
send one set of comments. Identify comments with the docket number 
found in brackets in the heading of this document. Received comments 
may be seen in the Division of Dockets Management between 9 a.m. and 4 
p.m., Monday through Friday, and will be posted to the docket at http://www.regulations.gov.

X. References

    The following references have been placed on display in the 
Division of Dockets Management (see ADDRESSES) and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday, 
and are available electronically at http://www.regulations.gov. (FDA 
has verified the Web site address in this reference section, but we are 
not responsible for any subsequent changes to the Web site after this 
document publishes in the Federal Register.)
    1. IMS Institute for Healthcare Informatics, ``The Use of Medicines 
in the United States: Review of 2011,'' April 2012 (available at http://www.imshealth.com/ims/Global/Content/Insights/IMS%20Institute%20for%20Healthcare%20Informatics/IHII_Medicines_in_U.S_Report_2011.pdf).
    2. Lester J., G. A. Neyarapally, E. Lipowski, et al., ``Evaluation 
of FDA Safety-Related Drug Label Changes in 2010,'' 
Pharmacoepidemiology Drug Safety, vol. 22, pp. 302-305, 2013.

List of Subjects

21 CFR Part 314

    Administrative practice and procedure, Confidential business 
information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 601

    Administrative practice and procedure, Biologics, Confidential 
business information.
    Therefore, under the Federal Food, Drug, and Cosmetic Act, the 
Public Health Service Act, and under authority delegated to the 
Commissioner of Food and Drugs, FDA proposes to amend 21 CFR parts 314 
and 601 as follows:

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG

0
1. The authority citation for 21 CFR part 314 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 356a, 
356b, 356c, 371, 374, 379e.

[[Page 67998]]

Sec.  314.70  [Amended]

0
2. Amend Sec.  314.70 as follows:
0
a. Revise paragraph (b)(2)(v)(C) introductory text;
0
b. Revise the paragraph (c) heading;
0
c. Add headings to paragraphs (c)(1) through (c)(7);
0
d. Revise paragraphs (c)(1), (c)(3), (c)(4), (c)(6) introductory text, 
(c)(6)(iii) introductory text, and (c)(7); and
0
e. Add new paragraph (c)(8).


Sec.  314.70  Supplements and other changes to an approved application.

* * * * *
    (b) * * *
    (2) * * *
    (v) * * *
    (C) Any change to the information required by Sec.  201.57(a) of 
this chapter other than changes under paragraph (c)(6)(iii) of this 
section, with the following exceptions that may be reported in an 
annual report under paragraph (d)(2)(x) of this section:
* * * * *
    (c) Changes requiring supplement submission at least 30 days prior 
to distribution of the drug product made using the change and certain 
changes being effected pending supplement approval (moderate changes).
    (1) Types of changes for which a supplement is required. A 
supplement must be submitted for any change in the drug substance, drug 
product, production process, quality controls, equipment, or facilities 
that has a moderate potential to have an adverse effect on the 
identity, strength, quality, purity, or potency of the drug product as 
these factors may relate to the safety or effectiveness of the drug 
product. A supplement also must be submitted for any change in the 
labeling to reflect newly acquired information of the type described in 
paragraph (c)(6)(iii) of this section. If the supplement provides for a 
labeling change under paragraph (c)(6)(iii) of this section, 12 copies 
of the final printed labeling must be included.
    (2) Changes requiring supplement submission at least 30 days prior 
to distribution of the drug product made using the change (changes 
being effected in 30 days). * * *
* * * * *
    (3) Explanation of basis for the change and supplement identifier. 
A supplement submitted under paragraph (c)(1) of this section is 
required to give a full explanation of the basis for the change and 
identify the date on which the change is to be made. The supplement 
must be labeled ``Supplement--Changes Being Effected in 30 Days'' or, 
if applicable under paragraph (c)(6) of this section, ``Supplement--
Changes Being Effected.'' The information listed in paragraphs 
(b)(3)(i) through (b)(3)(vii) of this section must be contained in the 
supplement.
    (4) Distribution of drug product pending supplement approval (for 
changes being effected in 30 days). Pending approval of the supplement 
by FDA, except as provided in paragraph (c)(6) of this section, 
distribution of the drug product made using the change may begin not 
less than 30 days after receipt of the supplement by FDA.
    (5) Limitations on distribution of drug product pending supplement 
approval (for changes being effected in 30 days). * * *
* * * * *
    (6) Changes requiring supplement submission prior to distribution 
of the drug product made using the change (changes being effected). The 
agency may designate a category of changes for the purpose of providing 
that, in the case of a change in such category, the holder of an 
approved application may commence distribution of the drug product 
involved upon submission to the agency of a supplement for the change. 
These changes include, but are not limited to:
    (i) * * *
    (ii) * * *
    (iii) Changes in the labeling to reflect newly acquired information 
to accomplish any of the following:
* * * * *
    (7) Effect of complete response letter for changes being effected 
supplement. If the agency issues a complete response letter to the 
supplemental application, the manufacturer may be ordered to cease 
distribution of the drug product(s) made with the manufacturing change 
or, if the supplemental application was submitted for a labeling change 
under paragraph (c)(6) of this section, the manufacturer must cease 
distribution of the drug product(s) accompanied by the revised 
labeling.
    (8) Equal applicability to application holders and abbreviated 
application holders. An application holder may submit to its approved 
application or abbreviated application a supplement described by 
paragraph (c)(6)(iii) of this section. FDA will promptly post on its 
Web site information regarding the labeling changes proposed in the 
changes being effected supplement. The applicant must verify that the 
correct information regarding the labeling changes proposed in the 
changes being effected supplement appears on FDA's Web site and must 
contact FDA within 5 business days of posting if the information is 
incorrect.
    (i) Contents of supplement. A supplement to an approved application 
or abbreviated application described by paragraph (c)(6)(iii) of this 
section must contain the following information:
    (A) The application number(s) of the drug product(s) involved;
    (B) A description of the labeling change proposed in the changes 
being effected supplement;
    (C) The basis for the labeling change proposed in the changes being 
effected supplement, including the data supporting the change or, if 
submitted under paragraph (c)(6)(iii)(E), the specific change requested 
by FDA;
    (D) A copy of the final printed labeling and current product 
labeling annotated with the labeling change proposed in the changes 
being effected supplement;
    (E) If the changes being effected supplement is submitted by an 
abbreviated application holder and approval of the application for the 
reference listed drug has not been withdrawn under Sec.  314.150 of 
this chapter, a statement confirming that the notice described in 
paragraph (c)(8)(ii) of this section has been sent to the application 
holder for the reference listed drug.
    (ii) Notice of labeling changes being effected. An abbreviated 
application holder must send notice of the labeling change proposed in 
the changes being effected supplement, including a copy of the 
information supporting the change (with any personally identifiable 
information redacted), to the application holder for the reference 
listed drug at the same time that the supplement to the abbreviated 
application is submitted to FDA, unless approval of the application has 
been withdrawn under Sec.  314.150 of this chapter. An application 
holder or any abbreviated application holder may submit (on its own 
initiative or in response to a request from FDA) a labeling supplement 
or correspondence to its application or abbreviated application, as 
applicable, regarding the proposed labeling changes.
    (iii) Distribution of revised labeling. Pending approval of the 
supplement by FDA, distribution of the drug product with the revised 
labeling may be made by an application holder or abbreviated 
application holder upon submission to FDA of the supplement, except 
that if FDA determines during its review period that the supplement 
does not meet the criteria described in paragraph (c)(6)(iii) of this 
section, the supplement will be converted to a prior approval 
supplement, and the manufacturer must cease distribution of the drug 
product(s) accompanied by the revised labeling.

[[Page 67999]]

    (iv) Conforming labeling requirements. Upon FDA approval of changes 
to the labeling of the reference listed drug or, if the application for 
the reference listed drug has been withdrawn, upon FDA approval of 
changes to the labeling of an abbreviated application that relied on 
the reference listed drug, any other abbreviated application holder 
that relied upon the reference listed drug must submit a supplement 
under paragraph (c)(6)(iii)(E) of this section with conforming labeling 
revisions within 30 days of FDA's posting of the approval letter on its 
Web site, unless FDA requires the abbreviated application holder's 
labeling revisions at a different time in accordance with sections 
505(o)(4) or 505-1 of the Federal Food, Drug, and Cosmetic Act.
* * * * *


Sec.  314.97  [Amended]

0
3. Revise Sec.  314.97 to read as follows:


Sec.  314.97  Supplements and other changes to an approved abbreviated 
application.

    (a) The applicant must comply with the requirements of Sec. Sec.  
314.70 and 314.71 regarding the submission of supplemental applications 
and other changes to an approved abbreviated application.
    (b) A supplement to an approved abbreviated application for a 
safety-related change in the labeling that is submitted under Sec.  
314.70(b) or (c)(6) will be approved upon approval of the same labeling 
change for the reference listed drug, except that if approval of the 
application for the reference listed drug has been withdrawn under 
Sec.  314.150, FDA may approve such a supplement to an approved 
abbreviated application.


Sec.  314.150  [Amended]

0
4. Amend Sec.  314.150 as follows:
0
a. In paragraph (b)(10)(i), remove the word ``or'';
0
b. In paragraph (b)(10)(ii), remove the period and replace with a 
semicolon followed by the word ``or''; and
0
c. Add paragraph (b)(10)(iii).


Sec.  314.150  Withdrawal of approval of an application or abbreviated 
application.

* * * * *
    (b) * * *
    (10) * * *
    (iii) Changes to the labeling for the drug product that is the 
subject of the abbreviated application under Sec.  314.70(c)(6)(iii) of 
this chapter.
* * * * *

PART 601--LICENSING

0
5. The authority citation for 21 CFR part 601 continues to read as 
follows:

    Authority: 15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353, 
355, 356b, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 
216, 241, 262, 263, 264; sec 122, Pub. L. 105-115, 111 Stat. 2322 
(21 U.S.C. 355 note).
0
6. Amend Sec.  601.12 by revising paragraphs (f)(1), (f)(2)(i) 
introductory paragraph, and (f)(2)(ii); and by adding new paragraph 
(f)(2)(iii) to read as follows:


Sec.  601.12  Changes to an approved application.

* * * * *
    (f) * * * (1) Labeling changes requiring supplement submission--FDA 
approval must be obtained before distribution of the product with the 
labeling change. Except as described in paragraphs (f)(2) and (f)(3) of 
this section, an applicant shall submit a supplement describing a 
proposed change in the package insert, package label, container label, 
or, if applicable, a Medication Guide required under part 208 of this 
chapter, and include the information necessary to support the proposed 
change. The supplement shall clearly highlight the proposed change in 
the labeling. An applicant may report the minor changes to the 
information specified in paragraph (f)(3)(i)(D) of this section in an 
annual report. The applicant shall obtain approval from FDA prior to 
distribution of the product with the labeling change.
    (2) Labeling changes requiring supplement submission--product with 
a labeling change that may be distributed before FDA approval. (i) An 
applicant shall submit, at the time such change is made, a supplement 
for any change in the package insert, package label, or container label 
to reflect newly acquired information to accomplish any of the 
following:
* * * * *
    (ii) Pending approval of the supplement by FDA, the applicant may 
distribute a product with a package insert, package label, or container 
label bearing such change at the time the supplement is submitted, 
except that if FDA determines during its review period that the 
supplement does not meet the criteria described in paragraph (f)(2)(i) 
of this section, the supplement will be converted to a prior approval 
supplement, and the manufacturer must cease distribution of the drug 
product(s) accompanied by the revised labeling. The supplement shall 
clearly identify the change being made and include necessary supporting 
data. The supplement and its mailing cover shall be plainly marked: 
``Special Labeling Supplement--Changes Being Effected.''
    (iii) FDA will promptly post on its Web site information regarding 
the labeling changes proposed in the changes being effected supplement. 
The applicant must verify that the correct information regarding the 
labeling changes proposed in the changes being effected supplement 
appears on FDA's Web site and must contact FDA within 5 business days 
of posting if the information is incorrect.
* * * * *

    Dated: November 5, 2013.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2013-26799 Filed 11-8-13; 11:15 am]
BILLING CODE 4160-01-P