[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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[[Page 64300]]
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withdrawn as of December 14, 2018.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, [email protected].
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