
[Federal Register Volume 83, Number 240 (Friday, December 14, 2018)]
[Proposed Rules]
[Pages 64299-64302]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-27098]


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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]


Withdrawal of Proposed Rule on Supplemental Applications 
Proposing Labeling Changes for Approved Drugs and Biological Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule; withdrawal.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is 
announcing the withdrawal of the proposed rule on ``Supplemental 
Applications Proposing Labeling Changes for Approved Drugs and 
Biological Products'' that published in the Federal Register of 
November 13, 2013. FDA is taking this action in light of concerns 
expressed by commenters and considerations regarding Agency resources. 
FDA is continuing to consider ways to improve the communication of 
important, newly acquired drug safety information to healthcare 
providers and the public and to facilitate efforts to keep drug product 
labeling up to date throughout the product lifecycle.

DATES: The proposed rule published November 13, 2013 (78 FR 67985), is 
withdrawn as of December 14, 2018.

ADDRESSES: For access to the docket, go to https://www.regulations.gov 
and insert the docket number found in brackets in the heading of this 
document into the ``Search'' box and follow the prompts, and/or go to 
the Dockets Management Staff, 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. 6270, Silver Spring, MD 20993-0002, 301-
796-3601, janice.weiner@fda.hhs.gov.

SUPPLEMENTARY INFORMATION: 

I. Background

    Under the Federal Food, Drug, and Cosmetic Act, the Public Health 
Service 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(c) and (d); 42 U.S.C. 
262). All drugs have risks, and healthcare 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, and may include new risks or new information 
about known risks. Accordingly, all holders of new drug applications 
(NDAs), abbreviated new drug applications (ANDAs), and biologics 
license applications (BLAs) are required to develop written procedures 
for the surveillance, receipt, evaluation, and reporting of 
postmarketing adverse drug experiences to FDA (see 21 CFR 314.80(b), 
314.98(a), and 600.80(b)). Application holders also must comply with 
applicable reporting and recordkeeping requirements, including 
submission of an annual report (which contains, among other things, 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 the 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 21 U.S.C. 
355(k) and 21 CFR 314.81).
    When new information becomes available that causes labeling to be 
inaccurate, false, or misleading, all drug and biological product 
application holders must take steps to change the content of their 
product labeling in accordance with Sec. Sec.  314.70, 314.97, and 
601.12 (21 CFR 314.70, 314.97, and 601.12) (see 21 CFR 201.56(a)(2); 
see also 21 U.S.C. 331(a) and (b) and 352(a), (f), and (j)). While all 
drug and biological product application holders have these obligations, 
under current regulations, the procedures available to ANDA holders to 
update the labeling of generic drugs differ in certain respects from 
the procedures available to NDA holders and BLA holders to update 
product labeling. In addition, there are limitations on the procedures 
available to NDA holders and BLA holders to make certain updates to the 
Highlights of Prescribing Information of drug and biological product 
labeling that are subject to the content and format labeling 
requirements described in Sec. Sec.  201.56(d) and 201.57 (21 CFR 
201.56(d) and 201.57) (commonly referred to as the ``Physician Labeling 
Rule'' (PLR) format).
    In the Federal Register of November 13, 2013 (78 FR 67985), FDA 
proposed 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 safety-
related information in advance of FDA's review of the change by 
submitting a ``changes being effected'' (CBE-0) supplement to FDA. A 
CBE-0 supplement is an exception to the general requirement for FDA 
approval of a prior approval supplement containing revised product 
labeling before distribution. The proposed rule, if finalized, would 
have enabled ANDA holders for generic drugs to independently update and 
promptly distribute revised product labeling to reflect certain types 
of newly acquired safety-related information, even though the revised 
labeling may temporarily differ from that of the corresponding 
reference listed drug (RLD or brand drug) upon submission of a CBE-0 
supplement to FDA. FDA's proposed revisions to its regulations to allow 
generic drug manufacturers to update product labeling through CBE-0 
supplements in the same manner as brand drug manufacturers were 
intended to improve communication of important, newly acquired drug 
safety information to healthcare providers and the public. The proposed 
rule, if finalized, also would have removed the limitation on 
submission of CBE-0 supplements by any application holder for certain 
changes to the Highlights of Prescribing Information in PLR-format 
product labeling. For further information about these and other 
proposed regulatory changes described in the proposed rule, see 78 FR 
67985.
    FDA received numerous comments on the proposed rule from a diverse 
group of stakeholders. In view of requests to meet with FDA to present 
alternatives to the proposed regulatory changes described in the 
proposed rule and to promote transparency, FDA held a public meeting on 
March 27, 2015, at which any stakeholder had the opportunity to present 
or comment on the proposed rule or any alternative proposals intended 
to improve communication of important, newly acquired drug safety 
information to healthcare professionals and the public. In the February 
18, 2015, document announcing the public meeting (80 FR 8577), FDA 
reopened the docket for the proposed rule until April 27, 2015, to 
receive submissions of additional written comments on the proposed rule 
as well as alternative proposals presented during the public meeting.
    Several comments supported finalizing the rule as originally 
proposed. Other comments supported the goals of the proposed rule, but 
expressed concern that temporary labeling differences between generic 
drugs and the corresponding brand drug could complicate healthcare 
decision making. Comments in support of the proposed rule maintained 
that it would enhance drug safety by making healthcare practitioners 
and the public aware of new safety-related information about a drug 
more quickly. Several comments also opined that tort liability for 
failure to adequately warn patients of a known hazard may be an 
incentive for drug manufacturers to ensure that their product labeling 
reflects the most current safety information.
    Comments in opposition to the proposed rule raised policy, legal, 
and cost considerations. A number of

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comments asserted that generic drug application holders do not 
generally receive or possess all the data necessary to evaluate 
postmarket safety information and to support safety-related labeling 
changes. Comments expressed concern that additional or different 
warnings in generic drug labeling, even if temporary, may undermine 
confidence in generic drugs and their therapeutic equivalence to the 
brand drug. Comments throughout the healthcare delivery system also 
expressed concern about the confusion that might result if there were 
different versions of safety labeling for multiple generic versions of 
the same drug until FDA decided whether to approve the labeling changes 
proposed in the CBE-0 supplements. Several comments asserted that the 
proposed rule would impose significant burdens on the generic drug 
industry that would necessarily increase the cost of generic drugs or 
lead to market exit, which may increase the risk of drug shortages. 
However, most concerns regarding economic impact focused on the 
increased risk of tort litigation against generic drug manufacturers 
and others in the healthcare system.

II. Withdrawal of the Proposed Rule

    Having reviewed the comments on the proposed rule and further 
considered the proposal, FDA is withdrawing the proposed rule on 
``Supplemental Applications Proposing Labeling Changes for Approved 
Drugs and Biological Products'' published in the Federal Register of 
November 13, 2013. The concerns raised in the comments reflect 
significant competing interests, and FDA acknowledges that the proposed 
rule, if finalized, would present significant potential downsides. In 
light of those potential downsides, the Agency does not believe that 
finalizing the proposed rule would be an appropriate use of Agency 
resources. Rather, the Agency believes that such resources would be 
better used on other efforts to improve the communication of important, 
newly acquired drug safety information to healthcare professionals and 
the public, as discussed in greater detail below.
    The withdrawal of this proposed rule does not alter the ongoing 
obligation under FDA's current regulations for all holders of marketing 
applications for drug and biological products--including ANDA holders--
to ensure their product labeling is accurate, and not false or 
misleading, and to take steps to update their product labeling when new 
information becomes available that causes the labeling to become 
inaccurate, false, or misleading (see Sec.  201.56(a)(2); see also 21 
U.S.C. 331(a) and (b) and 352(a), (f), and (j)). This obligation serves 
an important public health function because new information regarding 
the risks and benefits of a drug may become available over time from 
various sources, including from postmarketing adverse drug experience 
reports and published literature, and updates to product labeling may 
be necessary.
    In addition to the ongoing obligation described above, ANDA holders 
must generally maintain the same labeling as the RLD throughout the 
lifecycle of the generic drug product. ANDA holders can, however, 
propose certain updates to product labeling by submitting a prior 
approval supplement that contains adequate supporting information for 
the proposed change. FDA will determine whether the proposed labeling 
change is appropriate, and whether the labeling for the RLD and 
corresponding generic drug(s) should be revised. If the approval of the 
NDA for the RLD has been withdrawn at the NDA holder's request because 
the RLD is no longer being marketed and certain other conditions are 
satisfied (see 21 CFR 314.150(c)), the NDA holder can no longer update 
labeling for the withdrawn RLD, but ANDA holders can still propose 
labeling updates through the submission of a prior approval supplement. 
In such cases, if FDA determines that the proposed labeling change is 
appropriate and approves the supplement, the Agency may request that 
other ANDA holders and any ANDA applicants relying on the same 
withdrawn RLD make the same updates (see FDA draft guidance for 
industry ``Updating ANDA Labeling After the Marketing Application for 
the Reference Listed Drug Has Been Withdrawn,'' 81 FR 44883, July 11, 
2016) (Draft Guidance on Updating ANDA Labeling) (Ref. 1).
    As noted, the proposed rule would have removed the current 
prohibition against the submission of CBE-0 supplements by NDA and BLA 
holders to change information in the Highlights of Prescribing 
Information portion of drug labeling. If an NDA holder or a BLA holder 
seeks to submit a CBE-0 supplement to change information in the 
Highlights of Prescribing Information to reflect newly acquired 
information for any of the reasons described in Sec.  314.70(c)(6)(iii) 
or Sec.  601.12(f)(2), as applicable, the NDA holder or BLA holder can 
normally obtain permission to do so under the current regulation by 
contacting FDA. 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 the limitation on submission of a 
CBE-0 supplement under 21 CFR 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).
    FDA is continuing to consider ways to improve the communication of 
important, newly acquired drug safety information to healthcare 
professionals and the public, and to facilitate efforts to keep drug 
product labeling up to date throughout the product lifecycle. Although 
the proposed rule focused on labeling updates to reflect newly acquired 
information related to drug safety, we recognize that there are general 
challenges for keeping generic drug labeling up to date when the RLD 
labeling is no longer being updated, including when FDA has withdrawn 
approval of the NDA for reasons other than safety or effectiveness. The 
Agency is actively evaluating ways to facilitate the updating of 
generic drug labeling to help ensure that drug labeling reflects the 
most current information. For example, FDA's fiscal year (FY) 2019 
Budget Request includes an investment to support efforts to update 
generic drug labeling, with an initial focus on oncology products, as 
part of the Agency's efforts to ensure that patients and their 
providers have access to up-to-date information to inform clinical 
decisions (Ref. 2). These efforts to ensure that more generic drugs 
have up-to-date product labeling reflecting the latest treatment 
information can also encourage wider adoption of generic drugs, 
broadening access to lower-cost alternatives to brand drugs for the 
American people.
    The withdrawal of this proposed rule does not preclude the Agency 
from reinstituting rulemaking concerning the issues addressed in the 
proposal. Should we decide to undertake such rulemaking in the future, 
we will re-propose the action and provide new opportunities for 
comment. Furthermore, this proposed rule is only intended to address 
the withdrawal of the proposed rule on ``Supplemental Applications 
Proposing Labeling Changes for Approved Drugs and Biological Products'' 
published in the Federal Register of November 13, 2013, and not any 
other pending proposals that the Agency has issued or is considering, 
including the Draft Guidance on Updating ANDA Labeling (Ref. 1) or the 
Agency's efforts to update the labeling of certain oncology drug 
products under FDA's FY2019 Budget Request (Ref. 2). If you need 
additional information about the subject matter of

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the withdrawn proposed rule, you may review the Agency's website 
(https://www.fda.gov) for any current information on the matter.

III. References

    The following references are on display at the Dockets Management 
Staff (see ADDRESSES) and are available for viewing by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also 
available electronically at https://www.regulations.gov. FDA has 
verified the website addresses, as of the date this document publishes 
in the Federal Register, but websites are subject to change over time.

    1. FDA, draft guidance for industry, ``Updating ANDA Labeling 
After the Marketing Application for the Reference Listed Drug Has 
Been Withdrawn,'' July 2016 (available at https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm510240.pdf).
    2. U.S. Department of Health and Human Services, Food and Drug 
Administration, ``Fiscal Year 2019 Justification of Estimates for 
Appropriations Committees'' (available at https://www.fda.gov/downloads/aboutfda/reportsmanualstorms/reports/budgetreports/ucm603315.pdf).

    Dated: December 10, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-27098 Filed 12-13-18; 8:45 am]
 BILLING CODE 4164-01-P


