Federal Register, Volume 76 Issue 243 (Monday, December 19, 2011)

[Federal Register Volume 76, Number 243 (Monday, December 19, 2011)]
[Rules and Regulations]
[Pages 78530-78540]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2011-32354]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 314

[Docket No. FDA-2011-N-0898]

Applications for Food and Drug Administration Approval To Market
a New Drug; Revision of Postmarketing Reporting Requirements--
Discontinuance

AGENCY: Food and Drug Administration, HHS.

ACTION: Interim final rule; request for comments.

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SUMMARY: The Food and Drug Administration (FDA or the Agency) is
issuing an interim final rule amending its postmarketing reporting
regulations implementing certain provisions of the Federal Food, Drug
and Cosmetic Act. The provisions of the Federal Food, Drug and Cosmetic
Act require manufacturers who are the sole manufacturers of certain
drug products to notify FDA at least 6 months before discontinuance of
manufacture of the products. This interim final rule modifies the term
``discontinuance'' and clarifies the term ``sole manufacturer'' with
respect to notification of discontinuance requirements. The broader
reporting resulting from these changes will enable FDA to improve its
collection and distribution of drug shortage information to physician
and patient organizations and to work with manufacturers and other
stakeholders to respond to potential drug shortages.

DATES: This interim final rule is effective January 18, 2012. Submit
either electronic or written comments on the provisions of this interim
final rule by February 17, 2012. Submit comments on the information
collection requirements under the Paperwork Reduction Act of 1995 by
January 3, 2012 (see the ``Paperwork Reduction Act of 1995'' section of
this document).

ADDRESSES: You may submit comments, identified by Docket No. FDA-2011-
N-0898 by any of the following methods, except that comments on
information collection issues under the Paperwork Reduction Act of 1995
must be submitted to the Office of 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:
Fax: (301) 827-6870.
Mail/Hand delivery/Courier (for paper, disk, 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-2011-N-0898 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 of this document.
Docket: For access to the docket to read background documents or
comments received, go to http://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 Division of
Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Kalah Auchincloss, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Silver Spring, MD 20993, (301) 796-0659, or Stephen
Ripley, Center for Biologics Evaluation and Research, Food and Drug
Administration, 1401 Rockville Pike, Rockville, MD 20852-1448, (301)
827-6210.

SUPPLEMENTARY INFORMATION:

I. Background

In the Federal Register of October 18, 2007 (72 FR 58993), we (FDA)
issued a final rule to revise our postmarketing reporting requirements
to implement section 506C of the Federal Food, Drug, and Cosmetic Act
(21 U.S.C. 356c). Section 506C of the Federal Food, Drug, and Cosmetic
Act (section 506C) requires manufacturers who are the sole
manufacturers of certain drug products to notify us at least 6 months
before discontinuance of manufacture of the products. Section 506C
applies to sole manufacturers of products that meet the following three
criteria:
1. The products are life supporting, life sustaining, or intended
for use in the prevention of a debilitating disease or condition;
2. The products are approved under section 505(b) or (j) of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(b) or (j)); and
3. The products are not originally derived from human tissue and
replaced by a recombinant product.
These three criteria are statutory requirements. FDA assesses
whether a drug is ``life supporting, life sustaining, or intended for
use in the prevention of a debilitating disease or condition'' on a
case-by-case basis, but intends to provide further guidance on this
issue in the near future.
Section 506C also requires us to distribute certain information
about covered discontinuances to appropriate physician and patient
organizations. Under section 506C, FDA may reduce the 6-month
notification period if we find good cause exists for the reduction.
Recent experience with drug shortages in the United States has
shown the serious and immediate impacts they can have on patients and
healthcare providers, particularly those shortages involving drugs that
are manufactured by a small number of firms and for which there are no
good therapeutic substitutes available. The number of drug shortages
annually has tripled from 61 in 2005 to 178 in 2010. Some shortages
delay or deny needed care for patients, because they involve critical
drugs used to treat cancer, to provide required parenteral nutrition,
or to address other serious medical conditions. Other shortages can
result in providers prescribing second-line alternatives, which may be
less effective and higher risk than first-line therapies. A survey of
1,800 health practitioners conducted by the Institute for Safe
Medication Practices (ISMP) concluded that drug shortages could lead to
medication errors and poor patient outcomes because shortages can
result in the use of secondary alternative therapies (Ref. 1).
In light of increasing concerns about the impact of drug shortages
on health care in the United States, on October 31, 2011, the President
issued Executive Order 13588 directing the FDA to ``take steps that
will help to prevent and reduce current and future disruptions in the
supply of lifesaving medicines'' and noting that ``one important step
is ensuring that the FDA and the public

[[Page 78531]]

receive adequate advance notice of shortages whenever possible'' (Ref.
2). In response to the Executive Order's directive to address the
growing drug shortage problem, this rule modifies the regulation at
Sec. 314.81(b)(3)(iii) (21 CFR 314.81(b)(3)(iii)), which, in addition
to Sec. 314.91 (21 CFR 314.91), implements section 506C of the Federal
Food, Drug, and Cosmetic Act.

II. Overview of the Interim Final Rule

This interim final rule adds two definitions to Sec.
314.81(b)(3)(iii)--a definition of ``discontinuance'' and a definition
of ``sole manufacturer.'' Although these terms were discussed in the
preamble to the final rule issuing Sec. 314.81(b)(3)(iii) published on
October 18, 2007 (72 FR 58993) (2007 Preamble), and have been used in
various documents informally expressing the Agency's interpretation of
section 506C and its implementing regulations (see, for example, the
Center for Drug Evaluation and Research (CDER) Manual of Policies and
Procedures 6003.1, Drug Shortage Management (Ref. 3)), these terms were
not defined in the regulation. Given the serious and growing threat to
public health due to drug shortages, the Agency believes it is
appropriate at this time to codify definitions of these terms. This
modification and clarification of our existing regulations will further
the public health objective of the Federal Food, Drug, and Cosmetic Act
as a whole, and section 506C specifically by increasing the scope of
information that FDA receives regarding discontinuances. This will
enable the Agency to: (1) Expand collection and distribution of
information on the discontinuance of certain drugs to appropriate
physician and patient organizations as required by section 506C(c); and
(2) work with manufacturers and other stakeholders to implement
appropriate strategies to reduce, to the greatest extent possible, the
public health impact of discontinuances of products that can lead to
drug shortages. We believe that clarification of terminology will also
improve statutory compliance.

A. Discontinuance

The Agency is revising an earlier policy position and defining the
term ``discontinuance'' in the regulation to include both permanent and
temporary interruptions in the manufacturing of a drug product, if the
interruption could lead to a disruption in supply of the product. This
interpretation of the statutory language best achieves the public
health purpose of section 506C and the Federal Food, Drug, and Cosmetic
Act as a whole.
Under section 506C, sole manufacturers are required to notify FDA
of a ``discontinuance'' of a drug product subject to section 506C. In
the 2007 Preamble, in response to a comment on the meaning of the term
discontinuance, we indicated that a discontinuance did not include
planned or unplanned temporary manufacturing cessations (72 FR 58993 at
58995, response to comment 4). At that time, we stated that only
manufacturers who intended to permanently discontinue manufacture and
marketing of the drug product were subject to mandatory reporting
requirements under section 506C. In our response to the comment in the
2007 Preamble, however, we did request that manufacturers who
experience an unplanned temporary manufacturing cessation keep the
Agency informed of the status of the shutdown because ``the duration of
an unplanned shutdown may be unpredictable and could affect the
availability of needed therapy for patients.''
FDA no longer believes that this narrow policy position regarding
the term ``discontinuance'' serves the public health need that the
Federal Food, Drug, and Cosmetic Act was intended to address. In 2007,
the Agency believed that the supply of drug product available to
patients during a temporary manufacturing cessation, particularly one
that was planned, would not be greatly affected during the interruption
in manufacturing. However, subsequent experience has shown that even
temporary discontinuances of manufacturing can have a significant
impact on patient access to drug products. For example, if an equipment
failure necessitates an unexpected temporary interruption in
manufacturing of a drug product subject to section 506C, this
discontinuance could have serious implications for patient access to
the product. Notification to FDA of such discontinuances will expand
FDA's ability to distribute information on the discontinuance of
certain drugs to physician and patient organizations and enable FDA to
work with manufacturers and other stakeholders to respond to potential
drug shortages.
The interim final rule therefore adds Sec. 314.81(b)(3)(iii)(d) to
provide that ``discontinuance'' means ``any interruption of
manufacturing of a drug product described in paragraph (b)(3)(iii)(a)
for sale in the United States that could lead to a potential disruption
in supply of the drug product, whether the interruption is intended to
be temporary or permanent.'' Thus the term ``discontinuance'' now
includes both temporary and permanent interruptions in manufacturing,
if the interruption could lead to a disruption in supply of the
product. This interpretation of ``discontinuance'' is consistent with
Webster's Third New International Dictionary, which defines the term to
mean ``cessation, shutdown, closure; interruption'' (Ref. 4). The
dictionary definition indicates that a discontinuance can be
interpreted to include both situations that are permanent (cessation,
shutdown, closure) and those that are temporary (interruption).
Any permanent discontinuance of manufacturing by a sole
manufacturer will lead, per se, to a disruption in supply of the
product; thus, all permanent discontinuances must continue to be
reported. Temporary discontinuances must be reported to the Agency
under this interim final rule only if the discontinuance could lead to
a disruption in supply of the product.
We understand that a manufacturer may be unable to report some
temporary discontinuances 6 months before the discontinuance, as
required by statute. When notification at least 6 months prior to the
discontinuance is impossible because it was unforeseen, the
manufacturer must notify the Agency as soon as possible after it knows
that a discontinuance will occur. For example, if a contamination
problem requires immediate shut down of a manufacturing plant for a
drug product subject to section 506C, the manufacturer will not be able
to provide the FDA with 6 months prior notification, but would be
required to notify FDA as soon as the manufacturer becomes aware that
the contamination necessitates a temporary discontinuance of
manufacture of the product.
Other circumstances that would trigger notification to the FDA of a
discontinuance of a drug product subject to section 506C include:
A business decision to permanently discontinue manufacture
of a drug product;
A delay in acquiring active pharmaceutical ingredients or
inactive ingredients that leads to, or could lead to, a temporary
interruption in manufacturing of a drug product while alternative
suppliers are located;
Equipment failure or contamination affecting the quality
of a drug product that necessitates an interruption in manufacturing
while the equipment is repaired or the contamination issue is
addressed;
Manufacturing shut-downs for maintenance or other routine
matters, if

[[Page 78532]]

the shut-down extends for longer than anticipated or otherwise could
disrupt supply of a drug product;
Conversely, a manufacturer is not required to notify FDA if a
discontinuance is part of the normal manufacturing schedule and is not
expected to lead to a disruption in supply of a drug product subject to
506C. For example, FDA need not be notified in the following
circumstances:
The manufacturer uses the same manufacturing plant to
manufacture two drug products, one of which (Product A) is subject to
section 506C. From January to June of each year the manufacturer uses
the plant to produce Product A. From July to December of each year the
manufacturer uses the plant to produce Product B. Although this could
be considered a temporary discontinuance of Product A from July to
December, because this is the usual manufacturing schedule and should
not therefore result in a disruption in the supply of Product A, the
manufacturer need not notify the Agency of the annual, temporary
discontinuance of Product A.
A manufacturer of a drug product implements a scheduled
shutdown of its manufacturing facility each year for routine
maintenance. The annual shutdown is anticipated and planned for in
advance; therefore, it is not expected to disrupt supply of a drug
product subject to 506C. The shutdown does not need to be reported to
the Agency under section 506C.
A manufacturer of a drug product subject to 506C
experiences an unexpected power outage that results in an unscheduled
interruption in manufacturing. The manufacturer expects to resume
normal operations within a relatively short timeframe and does not
expect a disruption in the supply of the drug product. The shutdown
does not need to be reported to the Agency under section 506C.
If any of the circumstances described above do lead to a disruption
in supply of the drug product, even if unanticipated, then it becomes a
reportable discontinuance under this rule and the manufacturer would be
required to notify FDA of a discontinuance of the product.
In addition to revising the definition of ``discontinuance,'' this
interim final rule makes a minor conforming change by striking the
phrase ``discontinuing manufacture'' in the first sentence of Sec.
314.81(b)(3)(iii)(a) and replacing it with the phrase ``discontinuance
of manufacture.'' This change ensures that the regulations contain an
appropriate cross-reference to the revised definition of
discontinuance.
The interim final rule also makes a minor change to the procedures
in Sec. 314.81(b)(3)(iii)(b) for reporting notices of discontinuances
to the Agency. The interim final rule requires manufacturers to report
a notice of a discontinuance to FDA either electronically or by
telephone according to instructions on the FDA's Drug Shortages Web
site at http://www.fda.gov/Drugs/DrugSafety/DrugShortages. Products
regulated by CDER must be reported to the CDER Drug Shortages
Coordinator. Products regulated by the Center for Biologics Evaluation
and Research (CBER) must be reported to the CBER Products Shortage
Coordinator. This change ensures that the appropriate offices are
timely notified of all relevant discontinuances. It also reflects
existing practice for submitting notices of discontinuance, and reduces
the burden on industry to submit multiple copies of the notification.

B. Sole Manufacturer

To best achieve the public health purposes of the Federal Food,
Drug, and Cosmetic Act, and section 506C, the Agency is clarifying the
term sole manufacturer to ensure that we receive timely reports of all
discontinuances of drug products subject to section 506C, including
where other strengths, dosage forms, or routes of administration of the
same drug product are marketed. The clarification is intended to
improve statutory compliance and to minimize instances where
manufacturers fail to make reports to the Agency as required by section
506C. This clarification of the statutory language best achieves the
purpose of section 506C and the Federal Food, Drug, and Cosmetic Act as
a whole.
Section 314.81(b)(3)(iii) currently does not include a definition
of the term ``sole manufacturer.'' In the 2007 Preamble, we rejected a
suggestion to rely on the ``Orange Book'' (FDA's publication on
``Approved Drug Products with Therapeutic Equivalence Evaluations'') as
the source for determining whether an entity is a sole manufacturer (72
FR 58993 at 58995, comment 3). The comment to the proposed rule had
expressed concern that, although the Orange Book lists all drug
products with approved new drug applications (NDA) and abbreviated new
drug applications (ANDA), it is not possible to determine whether the
listed approved products are, in fact, being manufactured. The comment
requested that we define sole manufacturer as ``an applicant listed in
the Orange Book who is the holder of the only listed approved
application under section 505(b) or (j) of the [FD&C] Act.'' We
declined to accept this definition of sole manufacturer, and reliance
on the Orange Book, to determine whether an applicant was a sole
manufacturer for several reasons in 2007, including the following: (1)
There may be delays in updating the Orange Book, rendering it
temporarily inaccurate; (2) the suggested definition could create
potential confusion because some drugs are approved but not marketed
and are therefore placed in the ``discontinued'' section of the Orange
Book; and (3) there are other generally reliable sources for obtaining
commercial manufacturing information to assist in determining whether
an applicant is a sole manufacturer.
We continue to believe that reference to the Orange Book is not the
appropriate way to identify a ``sole manufacturer'' for purposes of
implementing section 506C. In addition, we believe there has been some
confusion as to the scope of the term. Accordingly, the interim final
rule adds Sec. 314.81(b)(3)(iii)(d) to define ``sole manufacturer'' in
the regulation to mean ``an applicant that is the only entity currently
manufacturing a drug product of a specific strength, dosage form, or
route of administration for sale in the United States, whether the
product is manufactured by the applicant or for the applicant under
contract with one or more different entities.''
The definition in this interim final rule is intended to clarify
that a sole manufacturer means the only applicant currently supplying
the U.S. market with the drug product. It does not mean sole NDA or
ANDA holder. A manufacturer is considered a sole manufacturer even if
other manufacturers hold an approved NDA or ANDA for the same product,
if the other applicants are no longer manufacturing (or have never
manufactured) the product for sale in the United States. For example,
Company A holds an NDA for a drug product subject to section 506C and
manufactures and sells that product in the United States. Company B
holds an ANDA for the drug product, but does not manufacture or sell
the product in the United States. Company A would be considered a sole
manufacturer of the drug product for purposes of reporting a
discontinuance of the drug product under section 506C. If Company B
began manufacturing and selling the drug product in the United States,
then Company A would no longer be considered a sole manufacturer. A
manufacturer is responsible for determining if it is a sole
manufacturer under this regulation. There is commercial information
available to

[[Page 78533]]

help with this determination. If an applicant is unsure if it is a sole
manufacturer of a drug product subject to section 506C, FDA's drugs
shortages staff may be able to work with it to help it determine
whether it is or is not the sole manufacturer of the drug.
The interim final rule also clarifies that the specific strength,
dosage form, and route of administration of the product are critical in
determining if a manufacturer is a sole manufacturer. For example, if a
company manufacturers for sale in the United States an injectable
dosage form of a drug product subject to section 506C, that company is
considered a sole manufacturer of that drug product, even if a second
company manufactures and sells in the United States an oral dosage form
of the same drug product for the same indication. In this example, if
the second company was the only applicant manufacturing and selling the
oral dosage form in the United States, both companies would be
considered sole manufacturers for purposes of section 506C.
It is important that an entity currently manufacturing a drug
product of a specific strength, dosage form, or route of administration
for sale in the United States report a discontinuance to FDA because
that specific strength, dosage form, or route of administration may be
critical for the targeted needs of particular patients. To enable the
Agency to fully distribute information under section 506C(c), and to
work most effectively with manufacturers and other stakeholders to
implement appropriate strategies to reduce, to the greatest extent
possible, the public health impact of drug shortages, discontinuances
of a specific strength, dosage form, or route of administration of drug
products subject to section 506C must be reported to us. Moreover,
recent experience has shown that discontinuances of a specific
strength, dosage form, or route of administration of a drug product may
lead to a shortage of another strength, dosage form, or route of
administration of the product, compounding patient difficulties in
obtaining the drug product.
Finally, the new definition in the interim final rule clarifies who
bears the responsibility for reporting to FDA a discontinuance of a
drug product subject to section 506C. The inclusion of ``whether the
product is manufactured by the applicant or for the applicant under
contract with one or more different entities'' in the definition makes
clear that the application holder must report a discontinuance to FDA.
For purposes of section 506C, an application holder will be considered
a ``manufacturer'' even if the application holder contracts that
function out to another entity. The application holder is responsible
for establishing a process with any relevant contract manufacturer that
ensures the application holder's compliance with this rule. This could
include contractual terms between the application holder and the
contract manufacturer, as well as monitoring. For example, Company X
holds an NDA for a drug product subject to section 506C. Company X
contracts with Company Y to manufacture the drug product for the
purposes of marketing and selling the drug product in the United
States. Company X would be considered the ``sole manufacturer'' in the
above situation, and is required to establish a process with Company Y
that ensures Company X's ability to report a discontinuance of the drug
product to FDA.

III. Legal Authority

FDA is amending its postmarketing reporting regulations
implementing section 506C of the Federal Food, Drug, and Cosmetic Act
(21 U.S.C. 356c). Section 506C requires manufacturers who are the sole
manufacturers of certain drug products to notify us at least 6 months
before discontinuance of manufacture of the drug products. This interim
final rule modifies the term ``discontinuance'' and clarifies the term
``sole manufacturer'' with respect to section 506C notification
requirements. FDA's authority for this rule also derives from section
701(a) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 371(a)).
The Administrative Procedure Act permits an agency to promulgate a
rule without notice and comment procedures when an agency for ``good
cause finds (and incorporates the finding and a brief statement of
reasons therefor in the rules issued) that notice and public procedure
thereon are impracticable, unnecessary, or contrary to the public
interest'' (5 U.S.C. 553(b); 21 CFR 10.40(e)). FDA has determined that
good cause exists for this interim final rule and that notice and
comment procedures are contrary to the public interest given the
serious and growing threat to public health due to drug shortages.
Recent experience with drug shortages in the United States has
shown serious and immediate impacts on patients and healthcare
providers, particularly those shortages involving drugs that are
manufactured by a small number of firms and for which there are no good
therapeutic substitutes available. Some shortages delay or deny needed
care for patients, because they involve critical drugs used to treat
cancer, to provide required parenteral nutrition, or to address other
serious medical conditions. Other shortages can result in providers
prescribing second-line alternatives, which may be less effective and
higher risk than first-line therapies. The number of drug shortages
annually has tripled from 61 in 2005 to 178 in 2010. New shortages are
occurring at the present time.
The scope of information FDA receives under the current regulations
has not adequately enabled the Agency to distribute information on the
discontinuance of certain drugs to physician and patient organizations
as required by section 506C(c) and to work with manufacturers and other
stakeholders to respond to potential drug shortages. There are
significant non-quantifiable benefits of reporting information about
discontinuances to FDA, including better enabling the Agency,
manufacturers, healthcare providers, and patients to monitor and
evaluate these discontinuances to mitigate or prevent potential drug
shortages that can arise as a result of these discontinuances and that
could otherwise lead to serious and widespread adverse health
consequences. Any delay in the implementation of this rule would limit
the ability of healthcare providers to respond to potential and actual
shortages, and would reduce the ability of FDA to work with
manufacturers and other stakeholders to prevent and mitigate drug
shortages. In this instance, FDA has determined that an interim final
rule is legally permissible and in the public's interest.

IV. Analysis of Impacts

A. Introduction and Summary

1. Introduction
FDA has examined the impacts of the interim final 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). This interim final rule is a
significant regulatory action as defined by Executive Order 12866 and
accordingly has been reviewed by the Office of Management and Budget.
The Regulatory Flexibility Act requires agencies to analyze
regulatory

[[Page 78534]]

options that would minimize any significant impact of a rule on small
entities. The Agency projects that the interim final rule will not
likely have a significant economic impact on a substantial number of
small entities, but seeks comments on its analysis below.
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 $136 million, using the most current (2010) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
interim final rule to result in any 1-year expenditure that would meet
or exceed this amount.
2. Summary
The interim final rule modifies the term ``discontinuance'' and
clarifies the term ``sole manufacturer'' with respect to notifications
of discontinuance of products that are life supporting, life
sustaining, or intended for use in the prevention of a debilitating
disease or condition. The interim final rule will impose annual
reporting costs of up to $15,064 in total. Non-quantifiable benefits
include the value of the reported information about discontinuances in
helping FDA, manufacturers, healthcare providers, and patients to
monitor and evaluate these discontinuances to mitigate or prevent
potential drug shortages that can arise as a result of these
discontinuances and that could otherwise lead to serious and widespread
adverse health consequences.

B. Objective of and Need for the Interim Final Rule

Current regulations require that a sole manufacturer of a drug
product that is: (1) Life supporting, life sustaining, or intended for
use in the prevention of a debilitating disease or condition; (2)
approved under section 505(b) or 505(j) of the Federal Food, Drug, and
Cosmetic Act; and (3) not a product that was originally derived from
human tissue and was replaced by a recombinant product report permanent
discontinuances to FDA at least 6 months prior to the discontinuance.
FDA can reduce the 6-month notification period if the applicant submits
a certification of good cause, and the Agency finds good cause.
The purpose of the interim final rule is to define the terms
``discontinuance'' and ``sole manufacturer.'' In the interim final
rule, ``discontinuance'' is defined as ``any interruption in
manufacturing of a drug product described in paragraph (b)(3)(iii)(a)
for sale in the United States that could lead to a potential disruption
in supply of the drug product, whether the interruption is intended to
be temporary or permanent.'' ``Sole manufacturer'' is defined as ``an
applicant that is the only entity currently manufacturing a drug
product of a specific strength, dosage form, or route of administration
for sale in the United States, whether the product is manufactured by
the applicant or for the applicant under contract with one or more
different entities.'' These definitions will require additional
manufacturers to report to FDA a wider range of discontinuances that
could potentially lead to a drug shortage than under the current,
existing regulations.
While existing regulations require that only permanent
discontinuances be reported to FDA, in practice, some manufacturers
voluntarily notify FDA about temporary discontinuances. In the past 2
years, such notifications have enabled FDA to prevent 233 drug
shortages by expediting review of new manufacturing sites, new
suppliers, and specification changes. Nonetheless, recent data from
FDA's Drug Shortages Program (DSP) indicate that the number of drug
shortages has tripled from 2005 to 2010 (see figure 1 below, Ref. 5).
[GRAPHIC] [TIFF OMITTED] TR19DE11.002

A survey conducted by the American Hospital Association (AHA)
concluded that drug shortages are experienced by hospitals. For
example, almost 100 percent of the 820 hospitals surveyed had
experienced at least one drug shortage in the 6 months preceding the
survey (Ref. 6). Another survey of 1,800 health practitioners conducted
by the ISMP suggested that because drug shortages often result in the
need for physicians to prescribe alternative therapies which may be
less effective and higher risk than first-line treatments, drug
shortages can lead to the potential for medication errors and poor
patient outcomes as well as higher costs (Refs. 1 and 7).
The interim final rule is intended to increase the scope of
information that FDA receives, enabling the Agency to: (1) Expand
distribution of information on the discontinuance of certain drugs to
appropriate physician and patient organizations as required by section
506C(c); and (2) work with manufacturers and other stakeholders to
implement appropriate strategies to reduce, to the greatest extent
possible, the public health impact of discontinuances of products that
can lead to drug shortages. The public health purpose of section 506C
and the Federal Food, Drug, and Cosmetic Act as a whole are best
achieved with this modification to our existing regulations.

[[Page 78535]]

Currently it appears that some manufacturers may lack sufficient
incentives to either take steps to prevent certain shortages or to
notify FDA early enough for the Agency to act (Ref. 7). By providing
clear definitions, the interim final rule will address this concern and
require all applicants to report appropriate information to the Agency
in a timely manner.

C. Benefits

The interim final rule modifies the term ``discontinuance'' and
clarifies the term ``sole manufacturer'' with respect to postmarketing
reporting requirements of products subject to section 506C. The
clarification in terminology captures additional manufacturers as
``sole manufacturers'' by explicitly linking the definition of sole
manufacturer to a specific strength, dosage form, or route of
administration of a drug product. Requiring notification of temporary
discontinuances and clarifying the term sole manufacturer will result
in FDA receiving better and more timely information on a wider range of
discontinuances. This increased reporting will enable FDA to distribute
information on discontinuances to appropriate physician and patient
organizations and to work with manufactures and other stakeholders to
try to prevent a discontinuance from leading to a drug shortage, or to
mitigate the impacts of an unavoidable drug shortage on patients and
healthcare providers.
There is evidence that the negative impact of drug shortages could
be significant. For instance, the American Society of Health System
Pharmacists (ASHP) reported that annual labor costs to manage drug
shortages are approximately $216 million in the United States (Ref. 7).
Moreover, drugs in several major therapeutic classes are in shortage,
including oncology products, antibiotics, and electrolyte/nutrition
products. For example, statistics indicate that cancer alone affects
more than 11 million people in the United States (Ref. 8). Therefore,
the potential benefits of the interim final rule as a result of
prevention or mitigation of these drug shortages could be substantial
from both an economic and public health viewpoint. Because the shortage
of even one critical drug can impact a large number of patients and
healthcare providers, the potential benefits could be substantial even
if the interim final rule only results in a small number of additional
notifications of discontinuances to the Agency.

D. Costs

Currently, FDA receives one mandatory notification that meets the
statutory and regulatory criteria of a section 506C discontinuance per
year and zero certifications of good cause. In addition, there are
several dozen voluntary submissions of information to FDA that are
related to section 506C discontinuances but do not meet the applicable
statutory criteria, as implemented by the current regulation. We note
that as a result of FDA's letter to industry (Ref. 10), FDA has
experienced a significant increase in the number of notifications. We
estimate that the total number of manufacturers who would be required
to notify us of a discontinuance under the interim final rule would be
80 per year.\1\ However, the impact of the interim final rule
represents the incremental impact, which is the difference between the
total number of reports required by the interim final rule and the
baseline, i.e., the estimated number of reports that we would receive
without the interim final rule. We estimate that as a result of the
interim final rule, we will receive an additional 9 to 24 notifications
of section 506C discontinuances (both temporary and permanent
discontinuances) and 2 to 5 associated certifications of good cause. In
the 2007 Preamble, we estimated that it would take two hours to prepare
a notification of discontinuance and 16 hours to prepare a
certification of good cause (72 FR 58993 at 58999). Since neither the
format nor the content of these submissions will change as a result of
the interim final rule, we continue to estimate that it will take two
hours to prepare a notification of discontinuance and 16 hours to
prepare a certification of good cause. We estimate that it will take
longer to prepare a certification of good cause than a notification of
discontinuance because preparing a certification of good cause requires
a detailed narrative justifying a reduction in the notification period,
which is more labor intensive than the simpler notification of
discontinuance.
---------------------------------------------------------------------------

\1\ The total is estimated based on 220 shortages tracked by
FDA's CDER Drug Shortages Coordinator from January through October
of 2011, of which we estimate 30 percent would relate to
discontinuances subject to mandatory reporting under section 506C
and this interim final rule. The estimated number of discontinuances
subject to mandatory reporting (220 x 30 percent) is then adjusted
to include two additional months of reporting.
---------------------------------------------------------------------------

Notifications are generally prepared and submitted by a regulatory
affairs manager. Thus, labor hours are valued using the median hourly
wage for Management Occupations (occupation code 11-0000) in
Pharmaceutical and Medicine Manufacturing (North American Industry
Notification, NAICS, code 325400) as reported by the Bureau of Labor
Statistics 2010 Employment Occupational Statistics (Ref. 9). The median
hourly wage is $117, which is adjusted for benefits and overhead.
The estimated cost is $234 ($117 x 2 hours) per notification of
discontinuance, and $1,872 ($117 x 16 hours) per certification of good
cause. In table 1 below we present the estimated costs. The estimated
annual cost of the interim final rule is between $5,850 and $15,064.

Table 1--Estimated Additional Annual Reporting Costs of the Interim Final Rule
----------------------------------------------------------------------------------------------------------------
Number of
Type of response additional Hours per Cost per Total estimated
responses response response cost
----------------------------------------------------------------------------------------------------------------
Notification of Discontinuance (Sec. 9-24 2 $234 $2,106-$5,704
314.81(b)(3)(iii))...................................
Certification of Good Cause (Sec. 314.91)........... 2-5 16 $1,872 $3,744-9,360
---------------------------------------------------------
Total............................................. ........... ........... ........... $5,850-$15,064
----------------------------------------------------------------------------------------------------------------

E. Analysis of Regulatory Alternatives

The interim final rule will result in the submission of additional
notifications to FDA of a discontinuance of a drug product subject to
section 506C. As noted in FDA's recent report on medical product
shortages (Ref. 5), any system that increases reporting must ensure
that, in the pursuit of more ``signal,'' FDA is not overwhelmed with
``noise.'' We welcome comments on how the notifications can be designed
in line with this principle. Such an approach is consistent with
Section 4 of Executive Order 13563, which calls

[[Page 78536]]

upon agencies ``to identify and consider regulatory approaches that
reduce burdens and maintain flexibility and freedom of choice for the
public.'' FDA identified the following alternatives to the interim
final rule: (1) No change in regulation; and (2) publish guidance that
encourages sole manufacturers (including manufacturers of specific
strengths, dosage forms, and routes of administration) to notify FDA
about temporary discontinuances of drug products subject to the rule,
and (3) provide incentives for voluntary reporting.
1. Alternative 1: No Change in Regulation
A simple alternative would be to leave the current regulation
unchanged. While this alternative may not impose additional costs on
sole manufacturers of drug products subject to section 506C, the
benefits of this option would be uncertain and would not provide any
additional tools to reduce the number of product shortages.
2. Alternative 2: Publish Guidance
FDA could draft additional guidance to encourage voluntary
notification of upcoming discontinuances. A recent example is a FDA's
letter to industry (Ref. 10). However, such communications and guidance
cannot impose new regulatory requirements. Without this regulation
defining which manufacturers are required to notify FDA about both
temporary and permanent discontinuances of drug products subject to
section 506C, FDA may not have adequate information to distribute to
physician and patient organizations and to work effectively with
manufacturers and other stakeholders to better prevent and mitigate
drug shortages.
3. Alternative 3: Provide Incentives for Voluntary Reporting
It may be possible to develop a system of incentives to encourage
increased reporting on a voluntary basis. FDA welcomes comments from
the public on how such a system could be implemented, including the
types of incentives that would advance the FDA's mission to protect the
public health while encouraging additional reporting.

F. Regulatory Flexibility Analysis

FDA has examined the economic implications of the interim final
rule as required by the Regulatory Flexibility Act. The Agency projects
that the interim final rule will not likely have a significant economic
impact on a substantial number of small entities, but seeks comment on
its analysis below.
1. Economic Effect on Small Entities
The Small Business Administration (SBA) uses different definitions
of what a small entity is for different industries. Using SBA standard
size definitions, a firm categorized in NAICS code 315412
(Pharmaceutical Preparations) or NAICS code 325414 (Biological
Products) is considered small if it employs fewer than 750 or 500
people, respectively (Ref. 11). The most currently available data from
the 2007 Economic Census (Ref. 12) show that at least 92 percent of
these establishments would be considered small by SBA standards.\2\ We
note that using data at the establishment level implicitly assumes that
the typical manufacturing establishment is roughly equivalent to the
typical small manufacturing firm.
---------------------------------------------------------------------------

\2\ For NAICS code 325412, total value of shipments data are not
available for establishments employing fewer than 750 employees. The
estimated percent of small establishments (92 percent) is based on
the total number of establishments with fewer than 500 employees.
For NAICS code 324514 the percent of establishments with fewer than
750 employees is 96 percent.
---------------------------------------------------------------------------

We estimate that the cost per response as a percent of average
sales for manufacturers in NAICS code 325412 could represent up to
0.002 percent of sales. The greatest impact is on establishments hiring
fewer than 10 employees, where the cost per response as a percent of
average sales ranges from 0.029 percent to 0.235 percent. The analysis
of the effect on small versus large entities for NAICS 312314 is
limited by data restrictions imposed to safeguard the confidentially of
some establishments. Consequently, for NAICS code 312314 the average
value of shipments is only presented for all establishments. We
estimate that the cost per response as a percent of average sales in
this industry is between 0.001 percent and 0.004 percent (see table 2).
Therefore, the Agency concludes that this rule will not likely have a
significant impact on a substantial number of small entities, but we
request comments on our analysis.

Table 2--Estimated Economic Impact of Interim Final Rule on Small Entities
--------------------------------------------------------------------------------------------------------------------------------------------------------
Cost per response as a percent of average sales
Average value of ------------------------------------------------
Number of employees Number of Total value of shipments ($234 per response-- ($1,872 per response--
establishments shipments ($000) ($1,000) notification of certification of good
discontinuance) (%) cause) (%)
--------------------------------------------------------------------------------------------------------------------------------------------------------
NAICS Code 325412:
0-9........................................... 408 324,604 796 0.029 0.235
10-19..................................... 77 317,551 4,124 0.006 0.045
20-99..................................... 249 8,377,347 33,644 0.001 0.006
100-499................................... 182 32,516,961 178,665 0.000 0.001
500 and over.............................. 75 68,162,155 908,829 0.000 0.000
---------------------------------------------------------------------------------------------------------
All................................... 991 109,698,618 110,695 0.000 0.002
NAICS Code 325414:
All................................... 350 16,112,435 46,036 0.001 0.004
--------------------------------------------------------------------------------------------------------------------------------------------------------

2. Additional Flexibility Identified
In this section, we identify alternatives that would present
reductions in costs to small entities.
Alternative 1: Exempt Small-sized Entities: Exempting small-sized
businesses from the interim final rule would reduce the economic impact
to small businesses by up to 0.235 percent of average sales. However,
not imposing these notification requirements on drug products subject
to section 506C could

[[Page 78537]]

exacerbate the increasing trend in drug shortages that affect a
substantial number of patients and healthcare providers. Moreover,
these reporting requirements enable FDA to distribute information to
physician and patient organizations, to assess potential drug
shortages, and to evaluate mitigation strategies. Thus, exempting small
business entities may in the long-term lead to high social costs
associated with outcomes such as worsening of conditions for patients
for whom these products are necessary.
Alternative 2: Extend the Compliance Period for Small Businesses:
An alternative to reduce costs would be to extend the compliance period
for small-sized entities. While a longer compliance period may enable
small businesses to reduce labor costs, it would delay FDA's receipt of
notices of discontinuance and limit the Agency's ability to distribute
information to physician and patient organizations as required by
section 506C(c), to assess potential drug shortages, and to work with
manufacturers and other stakeholders to prevent or mitigate shortages.

V. Paperwork Reduction Act of 1995

This interim final rule contains information collection provisions
that are subject to review by OMB under the Paperwork Reduction Act of
1995 (44 U.S.C. 3501-3520) (the PRA). The title, description, and
respondent description of these provisions are shown below 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
each collection of information.
FDA invites comments on: (1) Whether the proposed collections of
information are 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 collections 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 collections of information on respondents,
including through the use of automated collection techniques, when
appropriate, or other forms of information technology.
Title: Applications for Food and Drug Administration Approval to
Market a New Drug; Revision of Postmarketing Reporting Requirements--
Discontinuance.
Description: Sections 314.81(b)(3)(iii) and 314.91 of FDA's
regulations (``Sec. 314.81(b)(3)(iii)'' and ``Sec. 314.91'',
respectively) implement section 506C. Section 314.81(b)(3)(iii)
requires entities who are the sole manufacturers of certain drug
products to notify us at least 6 months before discontinuance of
manufacture of the product. For the regulations to apply, a product
must meet the following three criteria:
1. The product must be life supporting, life sustaining, or
intended for use in the prevention of a debilitating disease or
condition;
2. The product must have been approved by FDA under section 505(b)
or 505(j) of the Federal Food, Drug, and Cosmetic Act; and
3. The product must not have been originally derived from human
tissue and replaced by a recombinant product.
Under Sec. 314.81(b)(3)(iii)(c), we will publicly disclose
information about drug products subject to section 506C that are to be
discontinued. Section 314.91 allows us to reduce the 6-month
notification period if we find that good cause exists for the
reduction. A manufacturer may request that we reduce the notification
period by certifying that good cause for the reduction exists.
In the October 18, 2007 final rule (72 FR 58993), we added
Sec. Sec. 314.81(b)(3)(iii) and 314.91 to our regulations. Sections
314.81(b)(3)(iii) and 314.91 require two new reporting requirements to
FDA that are subject to OMB approval under the PRA: Notification of
Discontinuance and Certification of Good Cause. The interim final rule
adds two new definitions to Sec. 314.81(b)(3)(iii): ``discontinuance''
and ``sole manufacturer.'' The interim final rule clarifies the scope
of manufacturers required to report and expands the range of
circumstances required to be reported to the Agency under Sec.
314.81(b)(3)(iii), but does not change the substantive content of the
reports required to be submitted to the Agency. This PRA analysis
covers the information collection resulting from the October 18, 2007
final rule and also includes our estimates of how the number of
Notifications of Discontinuance and Certifications of Good Cause may
increase as a result of this interim final rule. Accordingly, the
estimates included in the Analysis of Impacts will not directly match
the estimates in the PRA analysis because the PRA analysis represents
an estimate of the total reporting burden under Sec. Sec.
314.81(b)(3)(iii) and 314.91, while the Analysis of Impacts examines
only the increased costs and benefits as a result of the interim final
rule.

A. Notification of Discontinuance

Under Sec. 314.81(b)(3)(iii), at least 6 months before a sole
manufacturer intends to discontinue manufacture of a drug product
subject to section 506C, the manufacturer must send us notification of
the discontinuance. The notification of discontinuance generally
contains the name of the manufacturer, the name of the product to be
discontinued, the reason for the discontinuance, and the date of
discontinuance. We will work with relevant manufacturers during the 6-
month notification period to help minimize the effect of the
discontinuance on patients and health care providers, and to distribute
appropriate information about the discontinuance to physician and
patient organizations. The interim final rule adds definitions of
``discontinuance'' and ``sole manufacturer'' to Sec.
314.81(b)(3)(iii). The inclusion of these definitions expands
notification requirements under Sec. 314.81(b)(3)(iii) to additional
discontinuance circumstances and clarifies the scope of manufacturers
who must report discontinuances. The interim final rule also requires
that notifications of discontinuance be submitted either electronically
or by telephone according to instructions on FDA's Drug Shortage Web
site at http://www.fda.gov/Drugs/DrugSafety/DrugShortages. This change
ensures that the appropriate offices are timely notified of all
relevant discontinuances. It also reflects existing practice for
submitting notices of discontinuance, and reduces the burden on
industry to submit multiple copies of the notification.

B. Certification of Good Cause

We may reduce the 6-month notification period if we find good cause
for the reduction. As described in Sec. 314.91, a manufacturer can
request a reduction in the notification period by submitting written
certification that good cause exists to the following designated
offices: (1) The CDER Drug Shortage Coordinator at the address of the
Director of CDER; (2) the CDER Drug Registration and Listing Team,
Division of Compliance Risk Management and Surveillance in CDER; and
(3) the director of either the CDER division or the CBER office that is
responsible for reviewing the application. The following circumstances
may establish good cause:
A public health problem may result from continuation of
manufacturing for the 6-month period (Sec. 314.91(d)(1));

[[Page 78538]]

A biomaterials shortage prevents the continuation of
manufacturing for the 6-month period (Sec. 314.91(d)(2));
A liability problem may exist for the manufacturer if the
manufacturing is continued for the 6-month period (Sec. 314.91(d)(3));
Continuation of the manufacturing for the 6-month period
may cause substantial economic hardship for the manufacturer (Sec.
314.91(d)(4));
The manufacturer has filed for bankruptcy under chapter 7
or 11 of title 11, United States Code (Sec. 314.91(d)(5));
The manufacturer can stop making the product but still
distribute it to satisfy existing market need for 6 months (Sec.
314.91(d)(6)); or
Other good cause exists for a reduction in the
notification period (Sec. 314.91(d)(7)).
With each certification described previously, the manufacturer must
describe in detail the basis for its conclusion that such circumstances
exist. We require that the written certification that good cause exists
be submitted to the offices identified previously to ensure that our
efforts to address the discontinuance take place in a timely manner.
The interim final rule makes no changes to the requirements or process
for certification of good cause.
Description of Respondents: An applicant that is the sole
manufacturer and who is discontinuing manufacture of a drug product
that meets the following criteria: (1) Is life supporting, life
sustaining, or intended for use in the prevention of a debilitating
disease or condition; (2) was approved by FDA under section 505(b) or
(j) of the Federal Food, Drug, and Cosmetic Act; and (3) was not
originally derived from human tissue and replaced by a recombinant
product.
Burden Estimate: Table 3 of this document provides an estimate of
the annual reporting burden for notification of a product
discontinuance and certification of good cause under Sec. Sec.
314.81(b)(3)(iii) and 314.91, as amended by this interim final rule.
Notification of Discontinuance: Based on data collected from the
CDER Drug Shortage Coordinator since December 17, 2007, when Sec. Sec.
314.81(b)(3)(iii) and 314.91 went into effect, one manufacturer during
each year reported to FDA a discontinuance of one drug product meeting
the criteria of section 506C and its implementing regulations (i.e.,
the drug product was approved under section 505(b) or (j) of the
Federal Food, Drug, and Cosmetic Act, the drug product was ``life-
supporting, life-sustaining or intended for use in the prevention of a
debilitating disease or condition,'' the drug product was produced by a
sole manufacturer, and the drug product was permanently discontinued).
CDER's Drug Shortages Coordinator tracked 220 drug shortages between
January and October of 2011. The Agency estimates that 30 percent (66)
of these shortages would relate to discontinuances subject to mandatory
reporting under section 506C as a result of the interim final rule.
Adjusting to include an additional two months of reporting (November
and December), we estimate that FDA will receive a total of 80
notifications of a discontinuance per year under section 506C, as
amended by the interim final rule. Based on experience, a manufacturer
submits only one notification of a discontinuance per year, thus the
total number of manufacturers who would be required to notify us of a
discontinuance would be 80. Therefore, the number of respondents is
estimated to be 80. The hours per response is the estimated number of
hours that a respondent would spend preparing the information to be
submitted with a notification of product discontinuance, including the
time it takes to gather and copy the statement. Based on experience in
working with manufacturers to submit notifications under Sec.
314.81(b)(3)(iii), we estimate that approximately 2 hours on average
are needed per response. We do not expect the changes in the interim
final rule to affect the number of hours per response. Therefore, we
estimate that respondents will spend 160 hours per year notifying us of
a product discontinuance under these regulations.
Certification of Good Cause: Based on data collected from the CDER
drug shortage coordinator since 2007, one manufacturer each year
reported a discontinuance of one drug product under section 506C and
its implementing regulations. Each manufacturer has the opportunity
under Sec. 314.91 to request a reduction in the 6-month notification
period by certifying to us that good cause exists for the reduction.
The Agency has received no certifications of good cause since 2007.
Although we expect we will receive an increase in the number of reports
of discontinuances as a result of the changes in the interim final
rule, because of the limited circumstances under which good cause can
be requested or would be appropriately granted, we do not expect a
correspondingly large increase in the number of manufacturers
requesting a certification of good cause. We estimate that only 5
manufacturers will request a certification of good cause each year.
Therefore, the number of respondents is estimated to be 5. The total
annual responses are the total number of certifications of good cause
that are expected to be submitted to us in a year. We estimate that the
total annual responses will remain small, averaging one response per
respondent. The hours per response is the estimated number of hours
that a respondent spends preparing the detailed information certifying
that good cause exists for a reduction in the notification period,
including the time it takes to gather and copy the documents. We
estimate that approximately 16 hours on average are needed per
response. Therefore, we estimate that 80 hours will be spent per year
by respondents certifying that good cause exists for a reduction in the
6- month notification period under Sec. 314.91.

Table 3--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
Number of
21 CFR Section Number of responses per Total annual Hours per Total hours
respondents respondent responses response
----------------------------------------------------------------------------------------------------------------
Notification of Discontinuance.. 80 1 80 2 160
(314.81(b)(3)(iii)).............
Certification of Good Cause 5 1 5 16 80
(314.91).......................
-------------------------------------------------------------------------------
Total....................... 240
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.

[[Page 78539]]

The information collection provisions for this interim final rule
have been submitted to OMB for emergency review under the Paperwork
Reduction Act of 1995. An agency may not conduct or sponsor, and a
person is not required to respond to, a collection of information
unless it displays a currently valid OMB control number.
Interested persons are requested to fax comments regarding the
information collection to the Office of Information and Regulatory
Affairs, OMB. 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) 395-5806, or emailed to [email protected]. All
comments should be identified with the title, ``Applications for Food
and Drug Administration Approval to Market a New Drug; Revision of
Postmarketing Reporting Requirements--Discontinuance.''

VI. Federalism

FDA has analyzed this interim final rule in accordance with the
principles set forth in Executive Order 13132. FDA has determined that
the rule does not contain policies that 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 has concluded
that the 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.

VII. Environmental Impact

The Agency has determined under 21 CFR 25.30(h) 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.

VIII. Comments

Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) either electronic or written comments regarding this
document. It is only necessary to send one set of comments. It is no
longer necessary to send two copies of mailed 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.

IX. References

The following references are 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. (FDA has verified all
Web site addresses, but FDA is not responsible for any subsequent
changes to the Web site after this document publishes in the Federal
Register).

1. Institute for Safe Medication Practices. Drug Shortages:
National Survey Reveals High Level of Frustration, Low Level of
Safety. ISMP Medication Safety Alert. Sept 23, 2010, available at
http://www.ismp.org/newsletters/acutecare/articles/20100923.asp,
accessed December 2011.
2. Executive Order 13588, Reducing Prescription Drug Shortages,
October 31, 2011, available at http://www.gpo.gov/fdsys/pkg/FR-2011-11-03/pdf/2011-28728.pdf accessed December 2011.
3. Center for Drug Evaluation and Research, Manual of Policies
and Procedures 6003.1, Drug Shortage Management, September 26, 2006,
available at http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ManualofPoliciesProcedures/ucm079936.pdf, accessed December
2011.
4. Webster's Third New International Dictionary of the English
Language Unabridged, 2002, defining ``discontinuance.''
5. Food and Drug Administration. A Review of FDA's Approach to
Medical Product Shortage, October 31, 2011, available at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/ucm275051.htm,
accessed December 2011.
6. American Hospital Association. AHA Survey on Drug Shortages,
available at http://www.aha.org/aha/content/2011/pdf/drugshortagesurvey.pdf, accessed December 2011.
7. Department of Health and Human Services. Assistant Secretary
for Planning and Evaluation. Economic Analysis of the Causes of Drug
Shortages, October 2011, available at http://aspe.hhs.gov/sp/reports/2011/DrugShortages/ib.shtml, accessed December 2011.
8. American Cancer Society. Cancer Facts & Figures 2011.
Atlanta: American Cancer Society; 2011, available at http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-029771.pdf, accessed December 2011.
9. Bureau of Labor Statistics. National Occupational Employment
and Wage Estimates. Occupational Employment Statistics, May 2010,
available at http://www.bls.gov/oes/current/oes_nat.htm, accessed
December 2011.
10. Food and Drug Administration. Letter to Industry, October
31, 2011, available at http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm277675.htm, accessed December 2011.
11. Small Business Administration. Table of Small Business Size
Standards Matched to North American Industry Classification System
Codes. November 2010, available at http://www.sba.gov/sites/default/files/Size_Standards_Table.pdf, accessed December 2011.
12. United States Census Bureau. 2007 Economic Census. Sector
31: Manufacturing: General Summary: Industry Statistics for
Subsectors and Industries by Employment Size: 2007, available at
http://factfinder.census.gov/servlet/IBQTable?_bm=y&-geo_id=&-fds_name=EC0700A1&-ds_name=EC0731SG3&-_lang=en, accessed December
2011.

List of Subjects in 21 CFR Part 314

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

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, 21 CFR part 314 is amended 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.

0
2. In Sec. 314.81, paragraph (b)(3)(iii)(a) is amended by removing the
phrase ``discontinuing manufacture'' and adding in its place the phrase
``discontinuance of manufacture''; by revising paragraph
(b)(3)(iii)(b); and by adding new paragraph (b)(3)(iii)(d) to read as
follows:

Sec. 314.81 Other postmarketing reports.

* * * * *
(b) * * *
(3) * * *
(iii) * * *
(b) Notifications required by paragraph (b)(3)(iii)(a) of this
section must be submitted to FDA either electronically or by phone
according to instructions on FDA's Drug Shortages Web site at: http://www.fda.gov/Drugs/DrugSafety/DrugShortages.
* * * * *
(d) For purposes of this section and Sec. 314.91, the terms
``discontinuance'' and ``sole manufacturer'' are defined as follows:
Discontinuance means any interruption in manufacturing of a drug
product described in paragraph (b)(3)(iii)(a) of this section for sale
in the United States that could lead to a potential disruption in
supply of the drug product, whether the interruption

[[Page 78540]]

is intended to be temporary or permanent.
Sole manufacturer means an applicant that is the only entity
currently manufacturing a drug product of a specific strength, dosage
form, or route of administration for sale in the United States, whether
the product is manufactured by the applicant or for the applicant under
contract with one or more different entities.
* * * * *

Dated: December 13, 2011.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2011-32354 Filed 12-15-11; 8:45 am]
BILLING CODE 4160-01-P