Document ID: FDA-2011-N-0898-0015
Agency: fda
Document Type: Proposed Rule
Title: Permanent Discontinuance or Interruption in Manufacturing of Certain Drug or Biological Products
Posted Date: 2013-11-04T05:00Z

[Federal Register Volume 78, Number 213 (Monday, November 4, 2013)]
[Proposed Rules]
[Pages 65904-65923]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2013-25956]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 20, 310, 314, and 600

[Docket No. FDA-2011-N-0898]
RIN 0910-AG88

Permanent Discontinuance or Interruption in Manufacturing of 
Certain Drug or Biological Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule; request for comments.

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SUMMARY: The Food and Drug Administration (FDA or the Agency) is 
proposing to amend its regulations to implement certain drug shortages 
provisions of the Federal Food, Drug, and Cosmetic Act (the FD&C Act), 
as amended by the Food and Drug Administration Safety and Innovation 
Act (FDASIA). The proposed rule would require all applicants of covered 
approved drugs or biological products--including certain applicants of 
blood or blood components for transfusion and all manufacturers of 
covered drugs marketed without an approved application--to notify FDA 
electronically of a permanent discontinuance or an interruption in 
manufacturing of the product that is likely to lead to a meaningful 
disruption in supply (or a significant disruption in supply for blood 
or blood components) of the product in the United States.

DATES: Submit either electronic or written comments on the provisions 
of this proposed rule by January 3, 2014. Submit comments on the 
information collection requirements under the Paperwork Reduction Act 
of 1995 (the PRA) by December 4, 2013 (see the ``Paperwork Reduction 
Act of 1995'' section).

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 PRA must be submitted to the 
Office of Information and Regulatory Affairs, Office of Management and 
Budget (OMB) (see the ``Paperwork Reduction Act of 1995'' section).

Electronic Submissions

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

Written Submissions:

    Submit written submissions in the following ways:
     Mail/Hand delivery/Courier (for paper or CD-ROM 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the Agency name 
and Docket No. 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., Bldg. 51, Rm. 6208, 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.

Table of Contents

I. Executive Summary
    A. Purpose of the Proposed Rule
    B. Summary of the Major Provisions of the Proposed Rule
    C. Summary of the Costs and Benefits of the Proposed Rule
II. Introduction
III. Description of the Proposed Rule
    A. Persons Subject to the Proposed Rule
    B. Products Subject to the Proposed Rule
    C. Notification of a Permanent Discontinuance or an Interruption 
in Manufacturing
IV. Legal Authority
V. Analysis of Impacts
    A. Introduction
    B. Summary
VI. Paperwork Reduction Act of 1995
VII. Federalism
VIII. Environmental Impact
IX. Comments
X. References

SUPPLEMENTARY INFORMATION: 

I. Executive Summary

A. Purpose of the Proposed Rule

    FDASIA (Pub. L. 112-144) significantly amended provisions in the 
FD&C Act related to drug shortages. Among other things, FDASIA amended 
section 506C of the FD&C Act (21 U.S.C. 356c) to require all 
manufacturers of certain drugs to notify FDA of a permanent 
discontinuance or an interruption in manufacturing of these drugs 6 
months in advance of the permanent discontinuance or interruption in 
manufacturing, or as soon practicable. FDASIA also added section 506E 
to the FD&C Act (21 U.S.C. 356e) requiring FDA to maintain a current 
list of drugs that are determined by FDA to be in shortage in the 
United States, and to include on that public list certain information 
about those shortages. Finally, FDASIA permits FDA to apply section 
506C to biological products by regulation, and requires FDA to issue a 
final rule implementing

[[Page 65905]]

certain drug shortages provisions in FDASIA by January 9, 2014.
    In accordance with FDASIA, FDA is issuing this proposed rule, which 
we believe will improve FDA's ability to identify potential drug 
shortages and to prevent or mitigate the impact of these shortages.

B. Summary of the Major Provisions of the Proposed Rule

    The proposed rule would modify FDA's regulations to implement 
sections 506C and 506E of the FD&C Act as amended by FDASIA.
    Proposed Sec. Sec.  310.306, 314.81(b)(3)(iii) (21 CFR 
314.81(b)(3)(iii)), and 600.82 would require all applicants of certain 
approved drugs or biological products,\1\ including applicants of blood 
or blood components for transfusion (``blood or blood components'') 
that manufacture a significant percentage of the U.S. blood supply, and 
all manufacturers of certain drugs marketed without an approved 
application (``unapproved drug manufacturers''), to notify FDA 
electronically of a permanent discontinuance or an interruption in 
manufacturing of the product that is likely to lead to a meaningful 
disruption in supply (for drugs and biological products other than 
blood or blood components) or a significant disruption in supply (for 
blood or blood components) of the product in the United States. 
Applicants \2\ would be required to notify FDA of a permanent 
discontinuance or an interruption in supply if the drug or biological 
product is a prescription product that is life supporting, life 
sustaining, or intended for use in the prevention or treatment of a 
debilitating disease or condition, including any such drug used in 
emergency medical care or during surgery, and excluding 
radiopharmaceutical products (referred to in this document as 
``covered'' drugs or biological products). The proposed rule would 
require notification to FDA at least 6 months prior to date of the 
permanent discontinuance or interruption in manufacturing, or, if 6 
months' advance notice is not possible, as soon as practicable 
thereafter, but in no case later than 5 business days after the 
permanent discontinuance or interruption in manufacturing occurs.
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    \1\ As used throughout this preamble, the term ``biological 
product'' refers to a biological product licensed under section 351 
of the Public Health Service Act, other than a biological product 
that also meets the definition of a device in section 201(h) of the 
FD&C Act (21 U.S.C. 321(h)).
    \2\ In this document, for the sake of convenience, we 
collectively refer to applicants holding an abbreviated new drug 
application (ANDA), new drug application (NDA), or biologics license 
application (BLA) and unapproved drug manufacturers subject to this 
proposed rule as the ``applicant'' (although we recognize that an 
unapproved drug manufacturer is not an applicant). We may also 
individually refer to the ANDA, NDA, and BLA applicant or unapproved 
drug manufacturer as needed, if the context requires distinguishing 
between these entities.
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    The proposed rule would also require FDA to issue a public 
noncompliance letter to an applicant for failure to notify FDA under 
the proposed rule; specify minimum information that must be included in 
the notification; codify FDA's current practice of publicly 
disseminating information on shortages and maintaining public lists of 
drugs and biological products in shortage (subject to certain 
confidentiality protections); and define the terms, ``drug shortage,'' 
``biological product shortage,'' ``meaningful disruption,'' 
``significant disruption,'' ``life supporting or life sustaining,'' and 
``intended for use in the prevention or treatment of a debilitating 
disease or condition.''
    Finally, the proposed rule would include a technical revision to 
Sec.  20.100 (21 CFR 20.100) (public disclosure regulations) to include 
a cross-reference to the disclosure provisions in in Sec. Sec.  
310.306, 314.81, and 600.82; and would remove Sec.  314.91 (21 CFR 
314.91) related to reducing the 6-month notification period for ``good 
cause,'' since it is no longer applicable under the FDASIA-revised 
section 506C.

C. Summary of the Costs and Benefits of the Proposed Rule

    The proposed rule would impose annual reporting costs of up to 
$16,576 on those applicants affected by the rule, and up to $441,000 on 
FDA in review costs. Undertaking mitigation strategies, as measured by 
labor resources, is estimated to cost FDA between $2.44 and $7.84 
million, and industry between $3.86 and $12.43 million. We also 
estimate annual costs for industry between $8.54 and $26.89 million 
associated with increasing production. Estimated total annual costs of 
the interactions between industry and FDA range between $14.99 and 
$47.62 million. Discounting over 20 years, annual quantified benefits 
from avoiding the purchase of alternative products, managing product 
shortages, and life-years gained, would range from $27.56 million to 
$86.77 million using a 3 percent discount rate, and from $27.50 million 
to $86.61 million using a 7 percent discount rate. The public health 
benefits, mostly nonquantified, include the value of information that 
would assist FDA, manufacturers, health care providers, and patients in 
evaluating, mitigating, and preventing shortages of drugs and 
biological products that could otherwise result in delayed patient 
treatment or interruption in clinical trial development.

II. Introduction

    Recent experience with shortages of drugs and biological products 
in the United States has shown the serious and immediate effects they 
can have on patients and health care providers. According to 
information from FDA's drug and biological product shortages databases, 
the number of drug and biological product shortages quadrupled from 
approximately 61 in 2005 to more than 250 shortages in 2011. Although 
the number of drug shortages significantly decreased in 2012 to 117 
shortages, drug and biological product shortages still represent an 
ongoing challenge to public health.\3\ Shortages can involve critical 
drugs used to treat cancer, to provide required parenteral nutrition, 
or to address other serious medical conditions and can delay or deny 
needed care for patients. Shortages can also result in providers 
prescribing second-line alternatives, which may be less effective or 
higher risk than first-line therapies.
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    \3\ Information on drug shortages can be found at http://www.fda.gov/drugs/drugsafety/drugshortages/default.htm (drug 
shortages) and http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/Shortages/default.htm (biological product 
shortages).
---------------------------------------------------------------------------

    Preventing drug and biological product shortages is a top priority 
for FDA. Working closely with manufacturers and other stakeholders, FDA 
was able to help prevent just under 200 drug and biological product 
shortages in 2011 and more than 280 such shortages in 2012, using tools 
such as:
     Working with manufacturers to resolve manufacturing and 
quality issues contributing to short supply.
     Expediting FDA inspections and reviews of submissions from 
manufacturers to prevent and/or alleviate shortages.
     Identifying and working with manufacturers willing to 
initiate or increase production to cover expected gaps in supply.
     Exercising enforcement discretion in appropriate 
circumstances, if this would not cause undue risk to patients.
    In response to the increasing concerns about the impact of 
shortages on health care in the United States, on October 31, 2011, 
President Obama issued Executive Order 13588 directing 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

[[Page 65906]]

ensuring that FDA and the public receive adequate advance notice of 
shortages whenever possible'' (Ref. 1 of this proposed rule). In 
response to the Executive Order's directive to address the growing 
problem of drug shortages, FDA published an interim final rule (IFR) on 
December 19, 2011 (effective January 18, 2012), modifying the 
regulation at Sec.  314.81 related to drug shortages (76 FR 78530). As 
a result of the Executive Order and IFR, early notifications to FDA of 
potential shortages increased from an average of 10 a month before the 
Executive Order to approximately 60 a month in the months after the 
IFR. This dramatic increase in early notifications enabled FDA to work 
with manufacturers to successfully prevent numerous shortages. As we 
stated above, FDA was able to prevent just under 200 drug and 
biological product shortages in 2011 and more than 280 such shortages 
in 2012. Moreover, the number of new drug shortages decreased from more 
than 250 in 2011 to 117 in 2012--a 50 percent reduction.
    In July 2012, FDASIA amended the FD&C Act to modify existing drug 
shortages requirements and to add new drug shortages provisions. This 
rule proposes to implement the drug shortages provisions of FDASIA, 
and, when final, will supersede the IFR. Although many of the issues 
raised by the 11 comments we received on the IFR are no longer directly 
applicable to this rulemaking given the changes to the underlying 
statute made by FDASIA, when drafting this proposed rule we considered 
these comments to the extent that they were applicable.\4\ Where 
appropriate, we have summarized and responded to the IFR comments in 
this preamble.
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    \4\ The IFR comments are available electronically at http://www.regulations.gov, Docket No. FDA-2011-N-0898, or can be obtained 
in person at the Division of Dockets Management, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852.
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III. Description of the Proposed Rule

    Section 1001 of FDASIA made substantial changes to section 506C of 
the FD&C Act related to reporting and addressing ``permanent 
discontinuances'' or ``interruptions in manufacturing'' of certain drug 
products. Most significantly for purposes of this proposed rule, 
section 506C of the FD&C Act as amended:
     Requires all manufacturers of a prescription drug that is 
life supporting, life sustaining, or intended for use in the prevention 
or treatment of a debilitating disease or condition, including any such 
drug used in emergency medical care or during surgery, and excluding 
radiopharmaceutical products, to notify FDA of a permanent 
discontinuance in the manufacture of the drug or an interruption in the 
manufacturing of the drug that is likely to lead to a meaningful 
disruption in the supply of that drug in the United States at least 6 
months prior to the date of the permanent discontinuance or 
interruption in manufacturing, or, if that is not possible, as soon as 
practicable.
     Requires the manufacturer to include in the notification 
the reason for the permanent discontinuance or interruption in 
manufacturing.
     Requires FDA to issue a letter to a ``person'' who fails 
to comply with the notification requirements in section 506C.
     Defines the terms ``drug,'' ``drug shortage,'' and 
``meaningful disruption,'' and requires FDA to define the terms ``life 
supporting,'' ``life sustaining,'' and ``intended for use in the 
prevention or treatment of a debilitating disease or condition.''
     Permits FDA to apply section 506C to biological products, 
including vaccines and plasma-derived products and their recombinant 
analogs, if FDA determines the inclusion would benefit public health, 
taking into account existing supply reporting programs and aiming to 
reduce duplicative notifications.
     Requires FDA to distribute information on drug shortages 
to the public, to the maximum extent possible, subject to certain 
confidentiality protections.
    In addition to modifying section 506C, FDASIA added several new 
drug shortage-related sections to the FD&C Act, including section 506E. 
Section 506E of the FD&C Act requires FDA to maintain an up-to-date 
list of drugs that are determined by FDA to be in shortage, including 
the names and the National Drug Codes (NDCs) of such drugs in shortage, 
the name of each manufacturer of the drug, the reason for each shortage 
as determined by FDA (choosing from a list of reasons enumerated in the 
statute), and the estimated duration of each shortage. Section 506E of 
the FD&C Act also includes confidentiality provisions.
    This rule proposes to implement sections 506C and 506E of the FD&C 
Act by amending Sec.  314.81(b)(3)(iii) (permanent discontinuance or 
interruption in manufacturing of approved prescription drugs) and Sec.  
20.100 (cross-reference to disclosure provisions); adding new Sec.  
310.306 (permanent discontinuance or interruption in manufacturing of 
marketed prescription unapproved new drugs) and Sec.  600.82 (permanent 
discontinuance or interruption in manufacturing of prescription 
biological products); and removing Sec.  314.91 (reduction in the 
discontinuance notification period). Table 1 compares the proposed rule 
to the current regulation (IFR).
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    \5\ With respect to blood and blood components for transfusion, 
the reporting requirement applies only to an applicant that 
manufactures a significant percentage of the U.S. blood supply.

      Table 1--Current Regulation (IFR) Compared With Proposed Rule
------------------------------------------------------------------------
                                          Current
            Requirement               regulation (IFR)    Proposed rule
------------------------------------------------------------------------
Scope of products subject to         Sec.               Sec.   310.306.
 notification requirements.           314.81(b)(3)(iii  Sec.
                                      )(a).              314.81(b)(3)(ii
                                                         i)(a) and (f).
                                                        Sec.   600.82(a)
                                                         and (f).
                                     A drug product     All prescription
                                      approved under     drugs and
                                      an NDA or ANDA     biological
                                      that is:           products,
                                      Life       including
                                      supporting, life   marketed
                                      sustaining or      unapproved
                                      intended for use   prescription
                                      in the             drugs, that
                                      prevention of a    are:
                                      serious disease    Life
                                      or condition;      supporting,
                                      and.               life sustaining
                                      Not        or intended for
                                      originally         use in the
                                      derived from       prevention or
                                      human tissue and   treatment of a
                                      replaced by a      debilitating
                                      recombinant        disease or
                                      product..          condition,
                                                         including any
                                                         such drug used
                                                         in emergency
                                                         medical care or
                                                         during surgery;
                                                         and
                                                         That
                                                         are not
                                                         radiopharmaceut
                                                         ical
                                                         products.\5\

[[Page 65907]]

 
                                                        The terms ``life
                                                         supporting or
                                                         life
                                                         sustaining''
                                                         and ``intended
                                                         for use in the
                                                         prevention or
                                                         treatment of a
                                                         debilitating
                                                         disease or
                                                         condition'' are
                                                         defined in the
                                                         proposed rule.
What triggers notification.........  Sec.               Sec.
                                      314.81(b)(3)(iii   314.81(b)(3)(ii
                                      )(a) and (d).      i)(a) and (f).
                                                        Sec.
                                                         600.82(a)(1)
                                                         and (f).
                                     A                  For products
                                      ``discontinuance   other than
                                      ,'' defined as     blood or blood
                                      ``any              components, a
                                      interruption in    ``permanent
                                      manufacturing .    discontinuance'
                                      . . that could     ' or an
                                      lead to a          ``interruption
                                      potential          in
                                      disruption in      manufacturing
                                      supply of the      that is likely
                                      drug product [in   to lead to a
                                      the United         meaningful
                                      States], whether   disruption in
                                      the interruption   supply of the
                                      is intended to     product in the
                                      be temporary or    United
                                      permanent''.       States'';
                                                         ``meaningful
                                                         disruption'' is
                                                         defined in the
                                                         statute and the
                                                         proposed rule.
                                                        Sec.
                                                         600.82(a)(2)
                                                         and (f).
                                                        For blood or
                                                         blood
                                                         components, a
                                                         ``permanent
                                                         discontinuance'
                                                         ' or an
                                                         ``interruption
                                                         in
                                                         manufacturing
                                                         that is likely
                                                         to lead to a
                                                         significant
                                                         disruption in
                                                         supply of the
                                                         product in the
                                                         United
                                                         States'';
                                                         ``significant
                                                         disruption'' is
                                                         defined in the
                                                         proposed rule.
Who must notify FDA................  Sec.               Sec.
                                      314.81(b)(3)(iii   314.81(b)(3)(ii
                                      )(a) and (d).      i)(a).
                                                        Sec.
                                                         600.82(a).
                                     Applicants who     All applicants
                                      are sole           for covered,
                                      manufacturers of   approved drugs
                                      covered drugs;     and biological
                                      sole               products (other
                                      manufacturer is    than blood or
                                      defined in the     blood
                                      regulation.        components),
                                                         all applicants
                                                         for blood or
                                                         blood
                                                         components that
                                                         manufacture a
                                                         significant
                                                         percentage of
                                                         the U.S. blood
                                                         supply, and all
                                                         manufacturers
                                                         of covered
                                                         drugs marketed
                                                         without an
                                                         approved
                                                         application.
When to notify FDA.................  Sec.               Sec.
                                      314.81(b)(3)(iii   314.81(b)(3)(ii
                                      )(a).              i)(b).
                                                        Sec.
                                                         600.82(b).
                                     At least 6 months
                                      prior to the
                                      discontinuance.
                                     Sec.   314.91....   At
                                     Applicants may      least 6 months
                                      seek, and FDA      prior to the
                                      may grant, a       permanent
                                      reduction in the   discontinuance
                                      6-month            or interruption
                                      notification       in
                                      period for         manufacturing;
                                      ``good cause.''.   or
                                                         If
                                                         notification at
                                                         least 6 months
                                                         prior is
                                                         impossible,
                                                         ``as soon as
                                                         practicable,''
                                                         which is
                                                         further
                                                         described in
                                                         the proposed
                                                         rule.
                                                         Deletes
                                                         Sec.   314.91
                                                         in its
                                                         entirety,
                                                         because it is
                                                         no longer
                                                         applicable
                                                         under section
                                                         506C of the
                                                         FD&C Act as
                                                         amended by
                                                         FDASIA.
How to notify FDA..................  Sec.               Sec.
                                      314.81(b)(3)(iii   314.81(b)(3)(ii
                                      )(b).              i)(b).
                                                        Sec.
                                                         600.82(b).
                                     Electronically or  Electronically
                                      by phone,          in a format FDA
                                      according to       can process,
                                      instructions on    review, and
                                      FDA's drug         archive.
                                      shortages Web
                                      page.
What to include in the notification  Not specified....  Sec.
                                                         314.81(b)(3)(ii
                                                         i)(c).
                                                        Sec.
                                                         600.82(c).
                                                         Name,
                                                         NDC (or, for
                                                         certain
                                                         biological
                                                         products, an
                                                         alternative, as
                                                         applicable),
                                                         and applicant
                                                         of the product;
                                                         Whether
                                                         the
                                                         notification is
                                                         a permanent
                                                         discontinuance
                                                         or an
                                                         interruption in
                                                         manufacturing;
                                                         A
                                                         description of
                                                         the reason for
                                                         the permanent
                                                         discontinuance
                                                         or interruption
                                                         in
                                                         manufacturing;
                                                         and Estimated
                                                         duration of the
                                                         interruption in
                                                         manufacturing.
Dissemination of information.......  Sec.               Sec.
                                      314.81(b)(3)(iii   310.306(c).
                                      )(c).             Sec.
                                                         314.81(b)(3)(ii
                                                         i)(c).
                                                        Sec.
                                                         600.82(c).
                                     FDA will publicly  FDA will
                                      disclose a list    maintain public
                                      of all drug        lists of drugs
                                      products           and biological
                                      discontinued       products
                                      under Sec.         determined by
                                      314.81(b)(3)(iii   FDA to be in
                                      )(a).              shortage,
                                                         including the
                                                         names, NDCs
                                                         (or, for
                                                         certain
                                                         biological
                                                         products, an
                                                         alternative, as
                                                         applicable),
                                                         and each
                                                         applicant of
                                                         the product
                                                         (or, for
                                                         marketed
                                                         unapproved
                                                         prescription
                                                         drugs, each
                                                         manufacturer of
                                                         the product);
                                                         the reason for
                                                         the shortage;
                                                         and the
                                                         estimated
                                                         duration of the
                                                         shortage.
Confidentiality....................  Not specified in   Sec.
                                      regulation, but    314.81(b)(3)(ii
                                      information        i)(d)
                                      submitted to FDA  Sec.   600.82(d)
                                      under the         ................
                                      regulation is     Includes
                                      subject to         specific
                                      protections for    reference to
                                      trade secrets      protection of
                                      and confidential   trade secrets
                                      commercial and     and
                                      financial          confidential
                                      information        commercial
                                      where applicable.  information
                                                         submitted to
                                                         FDA under the
                                                         proposed rule
                                                         and allows FDA
                                                         to choose not
                                                         to make certain
                                                         other
                                                         information
                                                         public if it
                                                         determines that
                                                         would adversely
                                                         affect the
                                                         public health.
                                     No equivalent      Sec.
                                      provision.         20.100(c)(45).

[[Page 65908]]

 
                                                        Cross-reference
                                                         to disclosure
                                                         provisions in
                                                         Sec.  Sec.
                                                         310.306,
                                                         314.81, and
                                                         600.82.
Noncompliance......................  No equivalent      Sec.
                                      provision.         310.306(b).
                                                        Sec.
                                                         314.81(b)(3)(ii
                                                         i)(e).
                                                        Sec.
                                                         600.82(e).
                                                        If an applicant
                                                         of a covered
                                                         drug or
                                                         biological
                                                         product, or
                                                         manufacturer of
                                                         a covered,
                                                         marketed
                                                         unapproved
                                                         prescription
                                                         drug, fails to
                                                         submit a
                                                         notification
                                                         required under
                                                         the proposed
                                                         rule within the
                                                         required
                                                         timeframe, FDA
                                                         will issue a
                                                         publicly
                                                         available
                                                         noncompliance
                                                         letter to the
                                                         applicant or
                                                         unapproved drug
                                                         manufacturer.
------------------------------------------------------------------------

A. Persons Subject to the Proposed Rule

    Proposed Sec. Sec.  310.306, 314.81(b)(3)(iii), and 600.82 would 
require notification to FDA of a permanent discontinuance or an 
interruption in manufacturing of a covered drug or biological product. 
Under the proposed rule, the following persons would be subject to 
these notification requirements:
     All applicants with an approved NDA or ANDA for a covered 
drug product (proposed Sec.  314.81(b)(3)(iii)).
     All applicants with an approved BLA for a covered 
biological product, other than blood or blood components (proposed 
Sec.  600.82(a)(1)).
     Applicants with an approved BLA for blood or blood 
components, if the applicant is a manufacturer of a significant 
percentage of the U.S. blood supply (proposed Sec.  600.82(a)(2)).
     All manufacturers of a covered drug product marketed 
without an approved NDA or ANDA (proposed Sec.  310.306, which applies 
Sec.  314.81(b)(3)(iii) in its entirety to covered drug products 
marketed without an approved NDA or ANDA).
    Section 506C of the FD&C Act as amended by FDASIA requires a 
``manufacturer'' to notify FDA of a permanent discontinuance or an 
interruption in manufacturing. The proposed rule would require the 
ANDA, NDA, or BLA applicant (for approved drugs or biological products) 
or the unapproved drug manufacturer (for marketed, unapproved drugs) to 
notify FDA of a permanent discontinuance or an interruption in 
manufacturing.
    For purposes of section 506C of the FD&C Act, under the proposed 
rule an ANDA, NDA, or BLA applicant would be considered the 
manufacturer of an approved, covered product, even if the ANDA, NDA, or 
BLA applicant contracts that function out to another entity. In other 
words, the proposed rule makes clear that for approved, covered drugs 
and biological products, the ANDA, NDA, or BLA applicant bears the 
responsibility for reporting to FDA a permanent discontinuance or an 
interruption in manufacturing, whether the product is manufactured by 
the applicant itself or for the applicant under contract with one or 
more different entities.
    As such, the ANDA, NDA, or BLA applicant should establish a process 
with any relevant contract manufacturer, active pharmaceutical 
ingredient (API) supplier, or other nonapplicant that ensures the 
applicant's compliance with this proposed rule. For example, assume 
that Applicant X holds an ANDA, NDA, or BLA for a covered drug or 
biological product and contracts with a third party to manufacture the 
drug or biological product for the purposes of marketing and selling 
the drug or biological product in the United States. If the third party 
contract manufacturer experiences a manufacturing issue that results in 
a permanent discontinuance or an interruption in manufacturing of 
Applicant X's product that would be reportable under proposed Sec.  
314.81(b)(3)(iii) or Sec.  600.82, Applicant X, not the contract 
manufacturer, must notify FDA of this permanent discontinuance or 
interruption in manufacturing. Therefore, Applicant X should establish 
a process with the contract manufacturer that ensures Applicant X's 
ability to timely report to FDA the permanent discontinuance or 
interruption in manufacturing.
    Section 506C(i)(3) of the FD&C Act, as amended by FDASIA, directs 
FDA to ``take into account any supply reporting programs [for 
biological products] and . . . aim to reduce duplicative notification'' 
in applying section 506C to biological products by regulation. 
Accordingly, with respect to blood or blood components, we are 
proposing to limit this rule only to applicants that are manufacturers 
of a ``significant percentage of the United States blood supply.'' As 
described more fully in sections II.B.2.c and II.C.1.b.ii, FDA believes 
that this approach with respect to blood or blood components will 
ensure that the Agency receives information that is essential to 
preventing shortages of these products, without being unnecessarily 
duplicative of existing systems or unduly burdensome to industry. For 
purposes of this proposed rule, FDA intends to consider an applicant 
that holds a BLA for blood or blood components to be a manufacturer of 
a ``significant percentage'' of the U.S. blood supply if the applicant 
manufactures 10 percent or more of the U.S. blood supply (e.g., greater 
than 1.5 million units of whole blood annually or approximately 125,000 
units per month).

B. Products Subject to the Proposed Rule

1. Prescription Drug and Biological Products That Are Life Supporting, 
Life Sustaining, or Intended for Use in the Prevention or Treatment of 
a Debilitating Disease or Condition
    The proposed rule would apply to all prescription drug products 
approved under an NDA or ANDA (proposed Sec.  314.81(b)(3)(iii)), all 
marketed unapproved prescription drug products (proposed Sec.  
310.306), and all prescription biological products approved under a BLA 
(proposed Sec.  600.82) that are:
     Life supporting; life sustaining; or intended for use in 
the prevention or treatment of a debilitating disease or condition, 
including any such product used in emergency medical care or during 
surgery; and
     not radiopharmaceutical products.\6\
---------------------------------------------------------------------------

    \6\ With respect to blood and blood components for transfusion, 
the reporting requirement applies only to an applicant that 
manufactures a significant percentage of the U.S. blood supply.
---------------------------------------------------------------------------

    FDASIA does not define the terms ``life supporting,'' ``life 
sustaining,'' or ``intended for use in the prevention or treatment of a 
debilitating disease or

[[Page 65909]]

condition,'' but instead requires FDA to define them. Proposed 
Sec. Sec.  314.81(b)(3)(iii)(f) and 600.82(f) would define a ``life 
supporting or life sustaining'' drug product as one that is ``essential 
to, or that yields information that is essential to, the restoration or 
continuation of a bodily function important to the continuation of 
human life.'' This definition of ``life supporting'' or ``life 
sustaining'' is consistent with language used to describe this term in 
the preamble to the final rule implementing the pre-FDASIA section 506C 
(72 FR 58993 at 58994 (October 18, 2007)), and in medical device 
regulations (see 21 CFR 821.3(g)).
    Under the proposed rule, ``intended for use in the prevention or 
treatment of a debilitating disease or condition'' would refer to ``a 
drug product intended for use in the prevention or treatment of a 
disease or condition associated with mortality or morbidity that has a 
substantial impact on day-to-day functioning'' (proposed Sec. Sec.  
314.81(b)(3)(iii)(f) and 600.82(f)). We have equated ``debilitating 
disease or condition'' with ``serious disease or condition'' under this 
proposed definition and defined it according to the definition of 
``serious'' found in 21 CFR 312.300. This definition of ``intended for 
use in the prevention or treatment of a debilitating disease or 
condition'' is also consistent with our discussion of the term in the 
preamble to the proposed rule implementing the pre-FDASIA section 506C 
(65 FR 66665 at 66666 (November 7, 2000)).
    When defining these terms, we also took into account comments we 
received on the IFR, including: A request for additional clarity on how 
these terms relate to FDA's use of the term ``medically necessary'' 
with respect to drug and biological product shortages; comments 
recommending that FDA interpret this terminology to require 
notification for ``medicines at risk of being in shortage''; and a 
related comment suggesting that once FDA identifies ``medicines at risk 
of being in shortage,'' the Agency should establish a mechanism for the 
purchase and storage of advance supplies of drugs on the list. 
According to this comment, this ``government stockpile'' could prevent 
shortages from occurring or mitigate the impact of an unavoidable 
shortage.
    In response to the first comment, the proposed definitions of 
``life supporting or life sustaining'' and ``intended for use in the 
prevention or treatment of a debilitating disease or condition'' are, 
in important respects, different than FDA's definition of ``medically 
necessary'' as used in the context of the existing Center for Drug 
Evaluation and Research (CDER) Manual of Policies and Procedures (MAPP) 
on drug shortages (CDER MAPP 6003.1) (Ref. 2 of this proposed rule). 
FDA considers a product to be medically necessary under this internal 
MAPP if ``there is no other adequately available drug product that is 
judged by medical staff to be an appropriate substitute'' (Ref. 2 of 
this proposed rule). Under this proposed rule, the applicant would be 
required to notify FDA of a permanent discontinuance or an interruption 
in manufacturing of a drug or biological product that is life 
supporting, life sustaining, or intended for use in the prevention or 
treatment of debilitating disease or condition, whether or not the 
product is considered medically necessary under the MAPP. Under the 
MAPP, FDA uses the definition of medically necessary to prioritize the 
Agency's response to specific shortages or potential shortages and to 
allocate resources appropriately.
    In response to the second group of comments, the proposed rule does 
not define either ``life supporting or life sustaining'' or ``intended 
for use in the prevention or treatment of debilitating disease or 
condition'' to mean ``medicines at risk of being in shortage,'' because 
shortages are often triggered by factors related to manufacturing and 
product quality that cannot be anticipated in advance, making it 
difficult, if not impossible, to accurately predict drugs or biological 
products that are vulnerable to shortage. This suggested interpretation 
of these terms would also be inconsistent with the statutory text, 
which defines drugs subject to the notification provisions by their 
uses, and contains separate language to explain when risks to supply 
require a notification.
    Finally, in response to the suggestion to create a national 
stockpile of drugs and biological products vulnerable to shortage, FDA 
concludes that this is beyond the scope of the current proposal, which 
is to implement amended sections 506C and 506E of the FD&C Act.
    We are interested in comments on the definitions of ``life 
supporting or life-sustaining'' and ``intended for use in the 
prevention or treatment of a debilitating disease or condition.'' FDA 
believes these definitions are consistent with the industry's (and 
Agency's) current understanding of the terms, and that more information 
rather than less is essential for resolving drug shortages. However, we 
are specifically interested in comments on whether these definitions 
might unintentionally broaden the scope of reporting to such an extent 
that the Agency is ``over-notified,'' particularly in the context of 
the requirement for applicants to notify FDA of a meaningful disruption 
in the manufacturer's supply, without regard to the market as a whole 
(see section III.C.1. for further discussion on meaningful disruption 
in supply).
2. Biological Products
    Section 506C of the FD&C Act, as amended, states that for purposes 
of this section the term ``drug'' does not include biological products 
as defined in section 351(i) of the Public Health Service Act, unless 
the Secretary of Health and Human Services (the Secretary) applies 
section 506C to such products by regulation. Section 506C(i)(3) of the 
FD&C Act provides that FDA may, by regulation, apply section 506C to 
biological products, ``including plasma products derived from human 
plasma protein and their recombinant analogs'' if ``the Secretary 
determines that such inclusion would benefit the public health,'' 
taking into account ``any [existing] supply reporting programs'' and 
aiming to reduce ``duplicative notification.'' Additionally, FDA may 
apply section 506C of the FD&C Act to vaccines, but the Secretary must 
determine whether notification of a vaccine shortage to the Centers for 
Disease Control and Prevention (CDC) under its ``vaccine shortage 
notification program'' could satisfy a vaccine manufacturer's 
obligation to notify FDA of a permanent discontinuance or an 
interruption in manufacturing under section 506C.
    We are proposing to apply section 506C of the FD&C Act to all 
biological products, including recombinant therapeutic proteins, 
monoclonal antibody products, vaccines, allergenic products, plasma-
derived products and their recombinant analogs, blood or blood 
components, and cellular and gene therapy products. Like drug 
shortages, shortages of biological products can have serious negative 
consequences for patients who rely on these products for their 
treatment. For example, recent shortages of biological products such as 
agalsidase beta (Fabrazyme), peginterferon alfa-2a (Pegasys), and BCG 
\7\ Live (Intravesical) (TheraCys) have adversely affected patient 
care. Fabrazyme is indicated for the treatment of Fabry's disease, a 
life shortening, inherited disease caused by a deficiency of alpha-
galactosidase A, an enzyme needed to metabolize lipids. The Fabrazyme 
shortage resulted from contamination at the manufacturing

[[Page 65910]]

plant and led to rationing of the product at one-third the recommended 
dose for current patients using the drug. As a result of the reduced 
doses, some patients reported a progression of Fabry's disease, 
including serious adverse events affecting the heart, central nervous 
system, and kidneys. Similarly, shortages of the antiviral drug Pegasys 
and the bladder cancer biological drug TheraCys threatened the timely 
treatment of patients with debilitating diseases, interrupting the 
continuity (and potentially undercutting the effectiveness) of 
treatment for patients prescribed these medications as well as 
preventing new patients from obtaining these medications.
---------------------------------------------------------------------------

    \7\ BCG is an attenuated live culture preparation of the 
Bacillus of Calmette and Guerin (BCG) strain of Mycobaterium bovis.
---------------------------------------------------------------------------

    Early notification of a permanent discontinuance or an interruption 
in the manufacturing of biological products would allow FDA to address, 
prevent, or mitigate a shortage of these products, greatly benefiting 
the public health. In addition, for the reasons described in this 
document, we have determined that requiring manufacturers of biological 
products to notify FDA under this proposed rule would not duplicate the 
existing reporting programs of which we are aware.
    a. Plasma-derived products and their recombinant analogs. As stated 
previously, we are proposing to apply section 506C of the FD&C Act to 
all biological products, including plasma products derived from human 
plasma protein and their recombinant analogs (referred to in this 
document as plasma-derived products and their recombinant analogs). 
With respect to plasma-derived products and their recombinant analogs, 
FDA recognizes that the Plasma Protein Therapeutics Association (PPTA) 
has developed a voluntary data system that captures the distribution 
and supply of five plasma product groups in the United States: Plasma-
Derived Factor VIII, Recombinant Factor VIII, Immune Globulin (Ig), 
Albumin 5%, and Albumin 25%. The PPTA, in consultation with a third 
party, voluntarily submits a monthly report to FDA of aggregate 
distribution data for these five product groups. This information 
provides a picture of the total supply and distribution of these five 
products in any given month as compared to the last 12 months (see, 
e.g., http://www.pptaglobal.org/UserFiles/file/Sept2012PDfviii.pdf). 
(FDA has verified the Web sites in this document but is not responsible 
for any subsequent changes to the Web sites after this document 
publishes in the Federal Register.)
    FDA recognizes and greatly appreciates the efforts by PPTA to 
provide plasma product supply information to FDA and the public. 
However, in addition to the PPTA system, for several reasons we believe 
that it would benefit the public health for the Agency to receive 
direct notification under this proposed rule from all manufacturers of 
these products. First, the PPTA system does not include all plasma-
derived products and their recombinant analogs. FDA has approved many 
plasma-derived products (and their recombinant analogs) that are not 
included in the PPTA monthly report, but that would be subject to this 
proposed rule, such as Rho(D) Immune Globulin and Hepatitis B Immune 
Globulin; Coagulation Factor VIIa (Recombinant); and Coagulation Factor 
IX.
    Second, the product distribution data is submitted to PPTA (and 
subsequently to FDA) on a voluntary basis; reporting under this 
proposed rule would be mandatory. Finally, the PPTA data is aggregate 
distribution data derived from historical supply and demand. Unlike the 
notifications proposed under this rule, it is not real-time data, nor 
does it capture the types of circumstances that would be considered a 
``permanent discontinuance'' or an ``interruption in manufacturing'' 
under this proposed rule. Rather, as described previously, the PPTA 
data provides a snapshot of current aggregate supply as compared to 
historical supply. It is not intended to identify circumstances that 
could lead to a future permanent discontinuance or an interruption in 
manufacturing of all plasma-derived products and their recombinant 
analogs.
    Because the PPTA program, although helpful, does not serve the same 
purpose as notification under this proposed rule, including plasma-
derived products and their recombinant analogs in this rulemaking will 
not duplicate the PPTA system. FDA believes that including these 
products within the scope of the proposed rule is essential to FDA's 
efforts to identify permanent discontinuances and interruptions in 
manufacturing of these products, and consequently, essential to our 
efforts to address, prevent, or mitigate shortages of these products.
    b. Vaccines. We are proposing to apply section 506C of the FD&C Act 
to all biological products, including vaccines. Under section 
506C(i)(3)(B) of the FD&C Act, if FDA applies section 506C to vaccines, 
the Secretary must specifically consider whether the notification 
requirement may be satisfied by submitting a notification to CDC under 
CDC's ``vaccine shortage notification program.''
    CDC contracts with vaccine manufacturers as part of the Vaccines 
for Children (VFC) program.\8\ FDA recognizes that CDC includes 
language in its contracts with vaccine manufacturers requiring the 
manufacturer to notify CDC of vaccine supply issues that could affect 
the manufacturer's ability to fulfill its contract with CDC.\9\
---------------------------------------------------------------------------

    \8\ The VFC program is a federally funded program that provides 
vaccines at no cost to children and adults who might not otherwise 
be vaccinated because of inability to pay. VFC was created by the 
Omnibus Budget Reconciliation Act of 1993 as a new entitlement 
program to be a required part of each state's Medicaid plan. CDC 
buys vaccines at a discount from the manufacturers and distributes 
them to awardees--i.e., State health departments and certain local 
and territorial public health Agencies--who in turn distribute them 
at no charge to those private physicians' offices and public health 
clinics registered as VFC providers. (See http://www.cdc.gov/vaccines/programs/vfc/index.html.)
    \9\ The Biomedical Advanced Research and Development Authority 
(BARDA), which is responsible for the procurement of certain 
vaccines related to medical countermeasures, also includes similar 
language in its procurement contracts. Contracts for the procurement 
of medical countermeasures against chemical, biological, nuclear, 
and radiological threat agents (e.g. smallpox and anthrax vaccines) 
are administered by BARDA, part of the Office of the Assistant 
Secretary for Preparedness and Response in the U.S. Department of 
Health and Human Services (HHS). (See http://www.hhs.gov/aspr.)
---------------------------------------------------------------------------

    Only certain vaccines are included under the existing CDC program, 
and thus, only manufacturers of certain vaccines are obligated to 
provide notification of supply issues to CDC. Based on information from 
CDC, FDA estimates that approximately 30 percent of vaccines licensed 
in the United States are not subject to CDC notification, including 
vaccines for rabies, yellow fever, and typhoid.
    Moreover, even for the vaccines that are subject to CDC 
notification, the information collected is not adequate for purposes of 
this rule, because the existing CDC program does not require vaccine 
manufacturers to provide notice 6 months in advance of a permanent 
discontinuance or interruption in manufacturing. Early notice of 
permanent discontinuances and interruptions is critically important to 
the prevention of drug shortages. Although FDA and its HHS partners 
work together closely on vaccine supply issues, and the current 
framework for CDC notification is useful for contractual purposes, FDA 
believes including vaccines within the scope of this rulemaking is 
necessary to fully support FDA's efforts to identify, address, prevent, 
or mitigate a vaccine shortage and would not be duplicative of existing 
notification systems.
    c. Blood or blood components for transfusion. We are proposing to 
apply section 506C of the FD&C Act to blood

[[Page 65911]]

or blood components, but in a more limited manner than for other 
biological products. The proposed rule would require blood or blood 
component applicants (i.e., blood collection establishments subject to 
licensure) that manufacture a significant percentage of the U.S. blood 
supply to notify FDA of a permanent discontinuance or an interruption 
in manufacturing that is likely to lead to a ``significant disruption'' 
in the applicant's supply of blood or blood components. As described 
more fully in sections II.A and II.C.1.b.ii, the proposed rule is 
intended to require reporting of large-scale, permanent 
discontinuances, or interruptions in manufacturing of blood or blood 
components.
    The proposed rule would ensure that FDA receives information 
essential to the Agency in preventing, mitigating, or addressing 
shortages of blood or blood components, while avoiding duplication with 
existing programs that monitor local and regional supplies of blood or 
blood components by ABO blood group. We are aware of two significant 
efforts to monitor local and regional supplies of blood or blood 
components.
    i. America's Blood Centers and the Blood Availability and Safety 
Information System. America's Blood Centers (ABC) is a network of 
nonprofit community blood centers in North America. ABC members operate 
more than 600 blood collection sites in 45 states and provide blood or 
blood components to more than 3,500 hospitals and health care 
facilities. ABC also maintains a voluntary supply monitoring program 
for blood and blood components. Information on local and regional blood 
supply is provided weekly to ABC members nationwide through a 
newsletter, and online (see http://www.americasblood.org/stoplight.aspx). In addition, ABC and certain other large licensed 
blood establishments provide voluntary, daily blood supply reports to 
HHS, which maintains a system called the Blood Availability and Safety 
Information System (BASIS) (see https://www.usbloodreport.net/About.aspx). Certain sentinel hospitals also voluntarily provide 
inventory reports to the BASIS system, and these data are compiled into 
a weekly status report on blood supplies, stratified by ABO blood 
group. Upon request, FDA receives BASIS reports from HHS.
    The ABC and BASIS systems monitor the supply and demand of blood or 
blood components on a daily and weekly basis, and in the event of a 
national disaster. In other words, ABC and BASIS are tools for local 
blood centers and hospitals to track their day-to-day inventory of 
blood or blood components. Unlike the notifications required under this 
proposed rule, ABC and BASIS are not designed to predict large-scale or 
nationwide disruptions in the supply of blood or blood components. 
Moreover, ABC and BASIS are voluntary systems; the proposed rule would 
require mandatory reporting.
    ii. Task Force. Also critical to the management of the national 
blood supply is the coordinating function of the Interorganizational 
Task Force on Domestic Disasters and Acts of Terrorism (Task Force), 
which is managed by the AABB (formerly the American Association of 
Blood Banks). The Task Force was formed in January 2002 to help make 
certain that blood collection efforts resulting from domestic disasters 
and acts of terrorism are managed properly, and to deliver clear and 
consistent messages to the public regarding the status of the U.S. 
blood supply. The Task Force is comprised of representatives from blood 
establishments, trade associations, commercial entities, and liaisons 
from governmental Agencies (including FDA), who work together to ensure 
that adequate blood inventories are in place at all times. In addition, 
the Task Force operates a system for assessing the need for collections 
and transportation of blood components, should a disaster or act of 
terrorism occur.
    Again, the Task Force efforts, although critical to public health, 
are focused on inventory management and are not intended to predict 
large-scale disruptions in the supply of blood or blood components. The 
Task Force coordinates the movement of blood throughout the United 
States and appeals to the public for blood donations, but it is not 
sufficient for FDA in the context of predicting a permanent 
discontinuance or an interruption in manufacturing of these products 
that would have a large-scale impact.
    In short, although the information already available to FDA from 
the ABC, BASIS, and Task Force programs is useful, the existing 
frameworks are voluntary, do not result in a direct notification from 
an applicant to FDA, and, as explained previously, only capture short-
term, day-to-day supply and distribution information. In addition, in 
contrast to this proposed rule, the existing systems are not equipped 
to predict large-scale, significant disruptions of blood or blood 
components. Accordingly, FDA has determined that including blood or 
blood components within the scope of this rule would benefit the public 
health, providing information that is essential to FDA's efforts to 
address shortages of these products.
    However, recognizing that the existing ABC, BASIS, and Task Force 
programs do provide certain information concerning the supply of blood 
or blood components, we have limited the proposed reporting 
requirements to apply only to applicants of blood or blood components 
that manufacture a significant percentage of the U.S. blood supply, and 
only to a permanent discontinuance of manufacture or an interruption in 
manufacturing that is likely to lead to a ``significant disruption'' in 
supply of that blood or blood component, as further described in 
sections II.A and II.C.1.
    d. Distribution reports (for all biological products). Under Sec.  
600.81 (21 CFR 600.81), applicants are required to submit to the Center 
for Biologics Evaluation and Research (CBER) or CDER, information about 
the quantity of product distributed under the biologics license, 
including the quantity distributed to distributors. As part of this 
safety reporting requirement, manufacturers provide distribution data 
to FDA every 6 months or at other intervals as may be required by FDA. 
Although distribution reports submitted by applicants are helpful in 
the analysis of safety reporting data, particularly for newly approved 
products, these reports do not include information about a permanent 
discontinuance or an interruption of the manufacture of a biological 
product that is likely to lead to a meaningful disruption in the supply 
of that product. Furthermore, the production cycles of biological 
products vary widely (e.g., some are manufactured once a year, some are 
manufactured every other year, and some are manufactured more or less 
frequently), such that any distribution data received from the 
manufacturer at 6-month intervals for such products will not be 
current. Therefore, FDA has determined that the reporting requirements 
under Sec.  600.81 do not constitute a duplicate supply reporting 
program.
    In summary, we are proposing to apply section 506C of the FD&C Act 
to all biological products. For the reasons discussed in this document, 
FDA finds that this inclusion would benefit the public health by 
facilitating prompt FDA action to address, prevent, or mitigate drug 
shortages, without duplicating existing reporting programs or creating 
redundant reporting. With respect to vaccines, for the reasons already 
described, we have determined that notification to CDC is not 
sufficient for purposes of reporting to FDA under

[[Page 65912]]

section 506C of the FD&C Act and may not replace section 506C 
notifications.
3. Scope of the Term ``Product''
    For purposes of this proposed rule, ``product'' refers to a 
specific strength, dosage form, or route of administration of a drug or 
biological product. For example, if Applicant X experiences an 
interruption in manufacturing of the 50-milligram (mg) strength of a 
drug product that would be subject to proposed Sec.  314.81(b)(3)(iii), 
but the 100 mg strength continues to be manufactured without delay, 
under the proposed rule, Applicant X must notify FDA of the 
interruption in manufacturing of the 50 mg strength if the interruption 
is likely to lead to a meaningful disruption in the applicant's supply 
of the 50 mg strength. Recent experience has shown that the permanent 
discontinuance or interruption in manufacturing of a specific strength, 
dosage form, or route of administration of a drug or biological product 
can have a significant impact on the targeted needs of particular 
patients (e.g., although the 100 mg tablet from Applicant X is 
available, it may not be split in half easily for a patient that is 
prescribed the 50 mg strength).
    Moreover, shortages of a specific strength, dosage form, or route 
of administration may lead to a shortage of another strength, dosage 
form, or route of administration of the product, exacerbating patient 
difficulties in acquiring the product. Obtaining this information is 
consistent with the emphasis in the IFR on the importance of notifying 
FDA of permanent or temporary interruptions in supply of a specific 
strength, dosage form, or route of administration of covered products 
(76 FR 78530 at 78533), and with the general support for this approach 
we received in comments on the IFR.

C. Notification of a Permanent Discontinuance or an Interruption in 
Manufacturing

1. Notification
    a. Permanent discontinuance. Section 506C of the FD&C Act requires 
manufacturers to notify FDA of a permanent discontinuance of 
manufacture of a covered drug. Proposed Sec. Sec.  314.81(b)(3)(iii) 
and 600.82 would require the applicant to report all permanent 
discontinuances of covered drugs and biological products to FDA. For 
purposes of this rule, we are interpreting a permanent discontinuance 
to be a decision by the applicant for business or other reasons to 
cease manufacturing and distributing the product indefinitely.
    b. Interruption in manufacturing. In addition to permanent 
discontinuances, section 506C of the FD&C Act requires manufacturers to 
notify FDA of an interruption in manufacturing of a covered drug that 
is likely to lead to a meaningful disruption in supply of that drug in 
the United States. The statute defines ``meaningful disruption'' to 
mean ``a change in production that is reasonably likely to lead to a 
reduction in the supply of a drug by a manufacturer that is more than 
negligible and affects the ability of the manufacturer to fill orders 
or meet expected demand for its product; and does not include 
interruptions in manufacturing due to matters such as routine 
maintenance or insignificant changes in manufacturing so long as the 
manufacturer expects to resume operations in a short period of time'' 
(emphasis added).
    i. Drugs and biological products other than blood or blood 
components. Proposed Sec. Sec.  314.81(b)(3)(iii)(a) and 600.82(a)(1) 
would require the applicant for a product other than blood or blood 
components to report to FDA an interruption in manufacturing of the 
drug or biological product that is likely to lead to a meaningful 
disruption in supply of that drug or biological product in the United 
States. Proposed Sec. Sec.  314.81(b)(3)(iii)(f) and 600.82(f) would 
adopt the statutory definition of meaningful disruption in supply.
    Consistent with the statutory definition of meaningful disruption, 
the proposed rule would require an applicant to report an interruption 
in manufacturing likely to lead to a meaningful disruption in its own 
supply of a covered drug or biological product. In other words, when 
evaluating whether an interruption in manufacturing is reportable to 
FDA under this proposed rule, rather than considering the potential 
impact of the interruption on the market as a whole, the relevant 
question (regardless of how large or small the applicant's market share 
may be) is whether the interruption is likely to lead to a reduction in 
the applicant's supply of a covered drug or biological product that is 
more than negligible, and affects the ability of the applicant to fill 
its own orders or meet the expected demand of its clients for the 
covered product. Consistent with the statute, the proposed rule would 
not require an applicant to predict the market-wide impact of its own 
interruption in manufacturing, which can be difficult to accurately 
assess and could lead to inconsistent interpretation of the regulation, 
less accurate predictions, and under- or reporting, as suggested by 
multiple comments on the IFR.
    Under the proposed rule, reportable discontinuances or 
interruptions in manufacturing of a covered drug or biological product 
would include:
     A business decision to permanently discontinue manufacture 
of a covered drug or biological product.
     A delay in acquiring APIs or inactive ingredients that is 
likely to lead to a meaningful disruption in the applicant's supply of 
a covered drug or biological product while alternative API suppliers 
are located.
     Equipment failure or contamination affecting the quality 
of a covered drug or biological product that necessitates an 
interruption in manufacturing while the equipment is repaired or the 
contamination issue is addressed and that is likely to lead to a 
meaningful disruption in the applicant's supply of the product.
     Manufacturing shutdowns for maintenance or other routine 
matters, if the shutdown extends for longer than anticipated or 
otherwise is likely to lead to a meaningful disruption in the 
applicant's supply of a covered drug or biological product.
     A merger of firms or transfer of an application for a 
covered drug or biological product to a new firm, if the merger or 
transfer is likely to lead to a meaningful disruption in the 
applicant's supply of the product.
     An interruption in manufacturing (e.g., contamination of a 
manufacturing line) that in the applicant's view may not meaningfully 
disrupt the market-wide supply of the covered drug or biological 
product (for example, because the applicant holds only a small share of 
the market for the product), but that the applicant determines is 
likely to lead to a meaningful disruption in its own supply of the 
covered product.
    Conversely, an applicant would not be required under the proposed 
rule to notify FDA if an interruption in manufacturing is not likely to 
lead to a meaningful disruption in the applicant's supply of the drug 
or biological product. For example, FDA would not need to be notified 
in the following circumstances:
     A scheduled shutdown of an applicant's manufacturing 
facility for routine maintenance, if the shutdown is anticipated and 
planned for in advance; and therefore, is not expected to lead to a 
meaningful disruption in the applicant's supply of a covered drug or 
biological product.
     An unexpected power outage that results in an unscheduled 
interruption in manufacturing of a covered drug or biological product, 
if the applicant expects to resume normal operations

[[Page 65913]]

within a relatively short timeframe and does not expect to experience a 
meaningful disruption in its supply of the covered drug or biological 
product.
    In either of these circumstances, if the interruption in 
manufacturing subsequently appears likely to lead to a meaningful 
disruption in the applicant's supply of the covered drug or biological 
product, then it would become a reportable interruption in 
manufacturing under this proposed rule and the applicant would be 
required to notify FDA.
    The list of examples described in this document is intended to 
assist industry in understanding what would (or would not) be required 
to be reported under amended section 506C of the FD&C Act, but it is 
not exhaustive. The proposed rule would require any permanent 
discontinuance or any interruption in manufacturing that is likely to 
lead to a meaningful disruption in the applicant's supply of a covered 
drug or biological product to be reported to FDA, even if not 
specifically described in this preamble.
    ii. Blood or blood components for transfusion. Proposed Sec.  
600.82(a)(2) would require an applicant that manufactures a significant 
percentage of the U.S. blood supply to report to FDA an interruption in 
manufacturing of a blood or blood component that is likely to lead to a 
``significant disruption'' in supply of that product in the United 
States. As we discussed in section II.A, an applicant that manufactures 
10 percent or more of the U.S. blood supply (e.g., greater than 1.5 
million units of whole blood annually or approximately 125,000 units 
per month), would be considered to manufacture a significant percentage 
of the U.S. blood supply for purposes of this proposed rule. Proposed 
Sec.  600.82(f) defines ``significant disruption'' to mean ``a change 
in production that is reasonably likely to lead to a reduction in the 
supply of blood or blood components by a manufacturer that 
substantially affects the ability of the manufacturer to fill orders or 
meet expected demand for its product; and does not include 
interruptions in manufacturing due to matters such as routine 
maintenance or insignificant changes in manufacturing so long as the 
manufacturer expects to resume operations in a short period of time.'' 
This definition of significant disruption closely follows, but is not 
identical to, the statutory and regulatory definition of meaningful 
disruption.
    For purposes of the proposed rule, FDA intends to consider an 
interruption in manufacturing that leads to a reduction of 20 percent 
or more of an applicant's own supply of blood or blood components over 
a one-month period to ``substantially affect'' the ability of the 
applicant to fill orders or meet expected demand; accordingly, such an 
interruption would be considered a ``significant disruption'' in 
supply. Again, when determining when an interruption in manufacturing 
is likely to lead to a significant disruption in supply, the blood or 
blood component applicant should not consider the market as a whole, 
but rather, should consider only its own supply of product.
    The proposed definition of ``significant disruption'' (interpreted 
to mean affecting 20 percent or more of an individual applicant's 
supply over a one-month period) as applied to blood or blood 
components, in combination with the limitation of the proposed rule 
only to applicants of blood or blood components that manufacture a 
significant percentage (10 percent or more) of the nation's blood 
supply, is intended to avoid duplication with existing programs to 
monitor the daily and weekly distribution of blood or blood components 
described in section II.B.2.c. As described in that section, in 
general, existing programs maintained by ABC, BASIS, and the Task Force 
monitor and resolve temporary, local shortfalls of a particular ABO 
blood group or a particular blood component. Accordingly, the 
definition of ``significant disruption'' is intended to capture events 
that are likely to precipitate large-scale disruptions in an 
applicant's blood supply, and that are unlikely to be identified and 
corrected by the existing ABC, BASIS, and Task Force programs. The 
additional limitation of the proposed rule to applicants that 
manufacture a significant percentage of the nation's blood supply 
further ensures that reporting to FDA will not unnecessarily duplicate 
reporting to the ABC, BASIS, and Task Force systems, but still allows 
FDA to receive information that is essential to the Agency in 
preventing large-scale shortages of these products.
    Under the proposed rule, circumstances that would trigger 
notification to FDA of a permanent discontinuance or an interruption in 
manufacturing of blood or blood components would include the following 
examples. We recognize that, with the exception of the first example of 
a permanent discontinuance, the following interruptions are unlikely to 
be reasonably anticipated 6 months in advance. In that case they would 
be reportable as soon as practicable, but in no case later than 5 
business days after the interruption in manufacturing occurs:
     A business decision by an applicant that manufactures 10 
percent or more of the nation's blood supply to permanently discontinue 
manufacture of blood or blood components;
     A computer system failure that causes an applicant of a 
blood establishment that collects 10 percent or more of the nation's 
blood supply to be unable to label blood for 2 weeks, resulting in a 20 
percent monthly shortfall of blood for that applicant;
     An issue with blood collection bags, such that they are 
unavailable, causing an applicant that manufactures 10 percent or more 
of the nation's blood supply to experience a 20 percent monthly 
shortfall in normal production for that applicant;
     An issue with apheresis collection devices that causes an 
applicant of a blood establishment that collects 10 percent or more of 
the nation's blood supply to be unable to collect platelets by 
apheresis, resulting in a 20 percent monthly shortfall in platelet 
supply for that applicant;
     An explosion or fire that damages a large testing 
laboratory that performs blood testing for an applicant that 
manufactures 10 percent or more of the nation's blood supply, resulting 
in a 20 percent monthly shortfall of blood or blood components for that 
applicant.
    Conversely, a covered blood or blood component applicant would not 
be required under the proposed rule to notify FDA if an interruption in 
manufacturing is not likely to lead to a significant disruption in the 
applicant's supply of blood or blood components. For example, FDA would 
not need to be notified if a covered blood or blood component applicant 
experiences a temporary drop in blood donations at one of its local 
blood donation centers, such that it is unable to fully supply its 
hospital customers with blood for several days, provided the donation 
center quickly returns to its normal donation and supply levels and the 
dip in blood donations is not likely to lead to a 20 percent decrease 
in the applicant's overall supply of blood over a one-month period. We 
expect that this type of situation would be identified and resolved 
through the ABC, BASIS, and Task Force systems (e.g., these systems 
would identify the issue and locate temporary, alternative blood 
supplies for the applicant's customers). If such an event does lead to 
a significant disruption in a covered applicant's supply of blood or 
blood components, it would need to be reported to FDA under the 
proposed rule.

[[Page 65914]]

    Again, the list of examples described in this document is intended 
to assist industry in understanding what must be reported under amended 
section 506C of the FD&C Act, but the list is not exhaustive. The 
proposed rule would require any permanent discontinuance or any 
interruption in manufacturing that is likely to lead to a significant 
disruption (as defined by the proposed rule) in a covered applicant's 
supply of blood or blood components to be reported to FDA, even if not 
specifically discussed in this preamble.
    c. Consideration of comments to the IFR. Several comments on the 
IFR suggested alternative ways of defining circumstances that must be 
reported to FDA under pre-FDASIA section 506C of the FD&C Act. We have 
considered whether these may be relevant to amended section 506C of the 
FD&C Act. For example, one comment suggested that historical supply and 
demand should be considered when determining whether to notify FDA 
under section 506C of the FD&C Act. Specifically, the comment suggested 
that notification should only be required if an interruption in 
manufacturing is expected to affect the supply of the product based on 
``historical inventory levels and other factors.'' Another comment 
suggested that an applicant should be required to report to FDA only 
after the disruption in supply occurs, for example when it is ``unable 
to ship 90 percent or more of its full quantity of [covered] product as 
reasonably ordered by its customers for more than 4 weeks.'' In other 
words, the applicant should report to FDA if it experiences a 10 
percent reduction in supply for a 4-week period. A third comment 
suggested that notification should be required when an event causes an 
applicant to predict that patients will be unable to obtain a covered 
product for a certain, extended period of time (e.g., at the point when 
an applicant projects that it will be unable to ship the drug or 
biological product to customers for 8 weeks).
    Although we agree that it could be appropriate to consider 
historical supply and demand or shipping schedules in deciding whether 
a notification would be required under this proposed rule, we decline 
to limit the term ``interruption in manufacturing that is likely to 
lead to a meaningful disruption in supply'' to consideration only of 
such factors, and we decline to define the requirement by codifying a 
preset, numerical threshold. The purpose of FDASIA, and this proposed 
rule, is to improve FDA's ability to prevent or mitigate the impact of 
drug and biological product shortages by broadening the scope of 
information that the Agency receives regarding permanent 
discontinuances and interruptions in manufacturing. If reportable 
circumstances are limited to situations in which a manufacturer is 
unable to ship a certain percentage of historic demand for a certain 
period time, or unable to ship at all for a certain period of time, 
some circumstances that could lead to a shortage may not be reported to 
FDA, putting the Agency at a disadvantage in addressing those 
situations.
    For example, if notification under this proposed rule is triggered 
only by the inability of an applicant to ship at least 90 percent of 
its full quantity of a particular drug product as reasonably ordered by 
its customers for more than 4 weeks (10 percent reduction in supply), 
if an applicant were able to ship 92 percent of its supply (i.e., it 
experiences an 8 percent reduction in supply), the interruption would 
not be reportable to FDA. Yet this interruption in manufacturing may 
still have an impact on a patient's ability to obtain the product and 
could still lead to a product shortage that is ``more than 
negligible.''
    Instead, this proposed rule defines ``meaningful disruption in 
supply'' consistent with the statutory text, and this preamble provides 
examples of reportable interruptions in manufacturing as illustrations 
for industry. An applicant may, at its discretion, analyze historical 
supply and demand and estimate shipping schedules to help determine 
whether an interruption in manufacturing is likely to lead to a 
meaningful disruption in supply, but the applicant should not 
substitute a rigid calculation for a full consideration of all 
circumstances applicable to determining whether the change in 
production is reasonably likely to lead to a reduction in supply that 
is more than negligible and that affects the manufacturer's ability to 
fill orders or meet expected demand for its product.
2. Timing and Submission of Notification
    a. Timing of notification. Section 506C of the FD&C Act requires 
notification to FDA ``(1) at least 6 months prior to the date of the 
permanent discontinuance or interruption [in manufacturing]; or (2) if 
compliance with paragraph (1) is not possible, as soon as 
practicable.'' Consistent with the statute, proposed Sec. Sec.  
314.81(b)(3)(iii)(b) and 600.82(b) would require an applicant to notify 
FDA of a permanent discontinuance or an interruption in manufacturing 
at least 6 months in advance of the date of the permanent 
discontinuance or interruption in manufacturing; or, if 6 months' 
advance notice is not possible, as soon as practicable thereafter, but 
in no case later than 5 business days after the permanent 
discontinuance or interruption in manufacturing occurs.
    The Agency's most powerful tool for addressing drug and biological 
product shortages is early notification, which provides lead time for 
FDA to work with manufacturers and other stakeholders to prevent a 
shortage or to mitigate the impact of an unavoidable shortage. As such, 
we expect that applicants would provide 6 months' advance notice 
whenever possible. In particular, FDA believes that an applicant will 
generally know of a permanent discontinuance at least 6 months in 
advance, and in that case the applicant would be required to provide 
notification of a permanent discontinuance to FDA at least 6 months in 
advance. We understand that an applicant may not reasonably be able to 
anticipate certain interruptions in manufacturing that are likely to 
lead to a meaningful disruption in supply 6 months in advance. For 
example, if an applicant discovers fungal contamination that requires 
an immediate, temporary shutdown of its manufacturing plant for a 
covered product, the applicant will not be able to provide FDA with 6 
months' advance notice of the interruption in manufacturing. Instead, 
the proposed rule would require the applicant to notify FDA ``as soon 
as practicable,'' but in no case more than 5 business days after the 
interruption in manufacturing occurs. In this example, the applicant 
would need to notify FDA as soon as it reasonably anticipates that an 
interruption in manufacturing caused by fungal contamination is likely 
to result in a meaningful disruption in supply of the applicant's 
product. The applicant should not wait until it or its manufacturer 
begins rejecting or delaying fulfillment of orders for the product from 
available inventory (i.e., the applicant should not wait until the 
interruption in manufacturing actually begins to disrupt supply and 
affect patient access to the product).
    In our experience, even if it is not possible for an applicant to 
notify the Agency before a permanent discontinuance or an interruption 
in manufacturing occurs, it should generally be possible for the 
applicant to provide notice within a day or two, and it should always 
be possible for the applicant to notify the Agency no later than 5 days 
after the permanent discontinuance or interruption occurs, even in the 
event of a natural disaster

[[Page 65915]]

or some other catastrophic incident. Accordingly, the 5-day provision 
in our proposal represents a date certain after which FDA would be able 
to take action under section 506C(f) of the FD&C Act against an 
applicant for failure to comply with the notification requirements (see 
section II.C.5 of this document for further discussion of the 
consequences of failure to notify FDA). Additionally, an applicant that 
could have notified the Agency before five days had passed, but waited 
until the end of the 5-day period would be in violation of the proposed 
regulation. Consistent with the statutory intent, whenever possible, 
applicants would be required to provide us with advance notice, whether 
6 months' advance notice, or ``as soon as practicable'' thereafter 
(e.g., 3 months' advance notice).
    b. Submission of notification. Proposed Sec. Sec.  
314.81(b)(3)(iii)(b) and 600.82(b) would require an applicant to notify 
FDA of a permanent discontinuance or an interruption in manufacturing 
electronically in a format FDA can process, review, and archive. 
Applicants must email notifications to drugshortages@fda.hhs.gov (for 
products regulated by CDER) or cbershortage@fda.hhs.gov (for products 
regulated by CBER). In the future, the Agency may consider creating an 
electronic notification portal linked to the Agency's internal drug 
shortages database to facilitate submission of these notifications. 
Unless and until this portal is created, however, email notifications 
will be used.
    c. Reduction in notification period for ``good cause''. Under the 
pre-FDASIA section 506C(b), a manufacturer could seek, and FDA could 
grant, a reduction in the required 6-month advance notification period 
for ``good cause.'' The statute listed several reasons that would 
constitute ``good cause,'' including when continuing to manufacture the 
product for the full 6-month notification period could cause a public 
health problem or result in substantial economic or legal hardship for 
the manufacturer. The regulation at Sec.  314.91 implemented the pre-
FDASIA section 506C(b). Because section 506C of the FD&C Act as amended 
by FDASIA does not include an option for formally seeking a reduction 
in the 6-month advance notification period based on ``good cause,'' 
this rule proposes to eliminate Sec.  314.91 in its entirety.
3. Contents of the Notification
    Proposed Sec. Sec.  314.81(b)(3)(iii)(c) and 600.82(c) would 
require an applicant to include the following items in notifications 
submitted under section 506C(a) of the FD&C Act:
     The name of the drug or biological product subject to the 
notification, including the NDC for the drug or biological product (or, 
for a biological product that does not have an NDC, an alternative 
standard for identification and labeling that has been recognized as 
acceptable by the Center Director);
     The name of the applicant of the drug or biological 
product;
     Whether the notification relates to a permanent 
discontinuance of the drug or biological product or an interruption in 
manufacturing of the drug or biological product;
     A description of the reason for the permanent 
discontinuance or interruption in manufacturing; and
     The estimated duration of the interruption in 
manufacturing.
    FDA is proposing to require applicants to include the minimum 
information listed in this document in the initial notification to 
assist the Agency in complying with section 506E of the FD&C Act, which 
requires FDA to maintain a publicly available list of drugs in 
shortage, as described in section II.C.4 of this document. We recognize 
that the duration of an interruption in manufacturing can be difficult 
to accurately predict. The applicant should provide FDA with its best 
estimate of the expected duration of the interruption in manufacturing. 
If, after the initial notification is submitted, the estimated duration 
changes, the applicant should notify FDA of the new expected duration 
of the interruption in manufacturing so that FDA can respond 
appropriately. In addition, the applicant should include a detailed, 
factual description of the reason for the shortage in the notification 
to assist FDA in responding to the notification.
    In addition to the proposed required elements of the notification, 
applicants are encouraged to include any other information in the 
notification that may be helpful to the Agency in working with the 
applicant to resolve the permanent discontinuance or interruption in 
manufacturing. Such information could include the applicant's market 
share, inventory on hand or in distribution channels, allocation 
procedures and/or plans for releasing available product, copies of 
communications to patients and providers regarding the shortage (e.g., 
Dear Healthcare Professional letters), or initial proposals to prevent 
or mitigate the shortage. As appropriate, the Agency will also follow 
up with the applicant after the notification is submitted to obtain 
additional information and to work with the applicant to facilitate 
resolution of any shortage or potential shortage.
4. Public Lists of Products in Shortage
    Section 506E of the FD&C Act requires FDA to maintain a publicly 
available list of drugs (and biological products, if FDA applies 
section 506C to biological products by regulation) that are determined 
by FDA to be in shortage, including providing the names and NDCs of the 
drugs, the name of each manufacturer of the drug, the reason(s) for the 
shortage, and the estimated duration of the shortage. Section 
506C(h)(2) of the FD&C Act defines ``drug shortage'' to mean ``a period 
of time when the demand or projected demand for the drug within the 
United States exceeds the supply of the drug.'' For purposes of section 
506E of the FD&C Act, under the proposed rule, the ANDA, NDA, or BLA 
applicant would be considered the manufacturer of an approved drug or 
biological product, even if the ANDA, NDA, or BLA applicant contracts 
that function out to another entity.
    Section 506E of the FD&C Act further requires FDA to include on the 
drug shortages list the reason for the shortage, choosing from the 
following statutory list of categories:
     Requirements relating to complying with current good 
manufacturing practices (CGMPs);
     Regulatory delay;
     Shortage of an active ingredient;
     Shortage of an inactive ingredient component;
     Discontinuation of the manufacture of the drug;
     Delay in shipping of the drug; and
     Demand increase in the drug.
    Consistent with the statute, and with FDA's current practice, under 
proposed Sec. Sec.  310.306(b), 314.81(b)(3)(iii)(d), and 600.82(d), 
FDA would maintain publicly available lists of drugs and biological 
products that are determined by FDA to be in shortage, whether or not 
FDA has received a notification under this proposed rule concerning the 
product in shortage. Proposed Sec. Sec.  314.81(b)(3)(iii)(f) and 
600.82(f) adopt the statutory definition of drug shortage (substituting 
``biological product shortage'' for ``drug shortage'' in Sec.  
600.82(f)). Under the proposed rule, the shortages lists would include 
the following required statutory elements for drugs or biological 
products in shortage: Names and NDCs (or the alternative standard for 
certain biological products) of the drugs or biological products, names 
of each applicant, reason for each shortage, and estimated duration of 
each shortage.

[[Page 65916]]

    If FDA has received a notification under the proposed rule for the 
drug or biological product, FDA would consider the reason for the 
shortage supplied by the applicant in its notification, and, where 
applicable, other relevant information before the Agency, in 
determining how to categorize the reason for the shortage under the 
proposed rule. Consistent with the statute, the Agency, not the 
applicant, would be responsible for determining which categorical 
reason best fits a particular situation. FDA would generally choose the 
categorical reason that best fits the applicant's supplied description. 
To facilitate FDA's determination of the categorical reason for the 
shortage, under the proposed rule we would expect applicants to supply 
as many details and facts as possible concerning the reason for the 
permanent discontinuance or interruption in manufacturing when 
submitting a 506C notification. This information would also assist FDA 
in responding quickly to the notification. FDA works proactively with 
applicants and others experiencing issues that could lead to a product 
shortage. We are committed to working with industry to address any 
underlying quality or manufacturing issues, and we seek to avoid 
shutdowns and long-term interruptions in supply whenever possible to 
ensure continued patient access to vital safe and effective drugs and 
biological products.
    If FDA has not received a notification under the proposed rule, but 
becomes aware of a shortage through other means, FDA would consider 
information before the Agency when determining and choosing the reason 
for the shortage to be included on the public list.
    In addition to the list of statutory reasons for the shortage that 
FDA may choose from, we are also proposing to add an eighth category, 
entitled ``Other reason.'' We are proposing to add this category 
because the Agency believes that some quality or manufacturing problems 
that result in a shortage may not fit into any of the listed categories 
in the statute (e.g., not all quality concerns are the result of 
noncompliance with CGMPs). The Agency would only choose ``Other 
reason'' if none of the other listed reasons is applicable. For 
example, an interruption in manufacturing as a result of a natural 
disaster or other catastrophic loss would fall into the ``Other 
reason'' category. Moreover, as described in this document, although 
FDA may choose the ``Other reason'' category, the public shortages list 
would also include a brief summary of the reason for the shortage 
submitted by the applicant, thus providing additional information to 
the public on the cause of the shortage.
    As noted previously, the proposed rule would codify, consistent 
with FDASIA, FDA's current practice of maintaining public lists of 
drugs and biological products in shortage, available on FDA's Web site 
at http://www.fda.gov/drugs/drugsafety/drugshortages/default.htm (drug 
shortages) and http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/Shortages/default.htm (biological product 
shortages).
    FDA's current drug shortages list was reorganized after the 
enactment of FDASIA to begin implementing revised section 506E of the 
FD&C Act. The drug shortages list now includes six categories of 
information about each drug product on the list: Company (manufacturer 
of product and contact information); Product (name, strength, 
formulation, dosage, and NDC); Availability and Estimated Shortage 
Duration; Related Information (includes applicant's submitted 
description of reason for shortage); Shortage Reason (FDA-determined 
reason for the shortage, chosen from the list in proposed Sec. Sec.  
314.81(b)(3)(iii)(d)); and Date Updated (last date FDA updated the 
information for that particular product). The biological product 
shortage list includes similar information in fields for Product Name, 
Reason for Shortage, and Status.
    In reformatting and revising the drug shortages list and drafting 
this proposed rule, we considered several comments on the IFR and other 
suggestions from stakeholders to improve the Agency's public 
communication about shortages. We agree that communication between FDA 
and interested stakeholders, including industry, providers (such as 
physicians, pharmacists, and nurses), and patients, is an essential 
component of preventing and mitigating both drug and biological product 
shortages. FDA updates the drug and biological product shortages lists 
regularly, and strives to communicate in ``real-time'' so that patients 
and providers have the most current data available for planning 
purposes.
    Moreover, consistent with section 506D(d) of the FD&C Act, FDA is 
encouraging patients, providers, pharmacists, and other nonapplicants 
to communicate with the Agency about potential shortages or disruptions 
in supply via one of the following email addresses: 
drugshortages@fda.hhs.gov or cbershortage@fda.hhs.gov. FDA is already 
in frequent contact with third parties to collect and disseminate 
shortage-related information, and we hope the availability of these 
dedicated email addresses will further facilitate communication. We are 
continuing to work diligently to improve our drug and biological 
product shortages Web sites and to consider new methods for 
communicating with all stakeholders about shortages. We appreciate 
suggestions on how to do this more effectively.
5. Confidentiality and Disclosure
    In general, as required by section 506C(c) and 506E of the FD&C 
Act, and as described in this document, FDA will publicly disclose, to 
the maximum extent possible, information on drug shortages, including 
information provided by applicants in a notification of a permanent 
discontinuance or an interruption in manufacturing.
    Proposed Sec. Sec.  314.81(b)(3)(iii)(d) and 600.82(d) contain an 
exception to these provisions, stating that FDA may choose not to make 
information collected under the authority of this proposed rule 
available to the public on the drug or biological product shortages 
lists or under its general obligation to disseminate drug shortage 
information under section 506C(c) of the FD&C Act if the Agency 
determines that disclosure of such information would adversely affect 
the public health (such as by increasing the possibility of hoarding or 
other disruption of the availability of the drug or biological product 
to patients). These proposed provisions closely track the statutory 
language in sections 506C(c)(3) and 506E(c)(3) of the FD&C Act.
    In addition, proposed Sec. Sec.  310.306(c), 314.81(b)(3)(iii)(d), 
and 600.82(d) state that FDA will not provide on the public drug or 
biological product shortages lists or under section 506C(c) of the FD&C 
Act, information that is protected by 18 U.S.C. 1905 or 5 U.S.C. 
552(b)(4), including trade secrets and commercial or financial 
information that is considered confidential or privileged under 21 CFR 
20.61. These proposed provisions would ensure appropriate protection 
for commercial and trade secret information protected by other Federal 
law and are consistent with the statutory language in sections 506C(d) 
and 506E(c)(2) of the FD&C Act, which clarify that the information 
provisions in sections 506C and 506E do not alter or amend 18 U.S.C. 
1905 or 5 U.S.C. 552(b)(4). Additionally, by reference to section 506E 
of the FD&C Act, the Agency's obligation to disseminate to the public, 
to the maximum extent possible, drug shortage information under section 
506C(c) does not alter or

[[Page 65917]]

amend the protections afforded by 18 U.S.C. 1905 or 5 U.S.C. 552(b)(4). 
FDA is also proposing a technical amendment to Sec.  20.100 to include 
a cross-reference to Sec. Sec.  310.306, 314.81, and 600.82. Proposed 
Sec.  20.100 describes, by cross-reference to other regulations, the 
rules on public availability of certain specific categories of 
information.
    One comment on the IFR expressed concern that FDA had not discussed 
how the Agency would preserve the confidentiality of proprietary 
information reported to FDA in the context of (pre-FDASIA) section 506C 
notifications. The comment was specifically concerned that as FDA 
attempts to mitigate a potential drug shortage by contacting 
manufacturers to increase production, it might reveal confidential 
information, even if the interruption in manufacturing by the original 
manufacturer is only temporary. Proposed Sec. Sec.  
314.81(b)(3)(iii)(d) and 600.82(d) are intended to make clear that FDA 
will adhere to applicable laws to protect trade secrets and 
confidential commercial information as it works to mitigate or prevent 
a shortage.
6. Failure To Notify
    Proposed Sec. Sec.  310.306(b), 314.81(b)(iii)(3)(e), and 600.82(e) 
would require FDA to issue a noncompliance letter to an applicant (or, 
for a covered, unapproved drug, to a manufacturer) who fails to submit 
a section 506C notification as required under proposed Sec. Sec.  
314.81(b)(iii)(3)(a) and 600.82(a) within the timeframe stated in 
proposed Sec. Sec.  314.81(b)(iii)(3)(b) and 600.82(b). Consistent with 
the statute, as proposed in this rule, failure to notify FDA would 
include failure to timely notify FDA. For example, if FDA discovers 
that an applicant did not notify FDA of the permanent discontinuance of 
a covered drug or biological product 6 months in advance, even though 
the applicant anticipated the permanent discontinuance 6 months in 
advance, FDA would issue a noncompliance letter under this proposed 
rule. Similarly, if FDA determines that an applicant experienced a 
reportable interruption in manufacturing that it could not reasonably 
anticipate 6 months in advance, but the applicant failed to notify FDA 
``as soon as practicable,'' the proposed rule would require FDA to 
issue a noncompliance letter. Refer to section II.C.2.a of this 
document for a discussion of the required timing for section 506C 
notifications.
    As required by statute, the proposed rule would provide the 
applicant with 30 days from the date of issuance of the noncompliance 
letter to respond to the letter. The applicant's response must set 
forth the basis for noncompliance and provide the required notification 
with the required information. Under the proposed rule, not later than 
45 days after the date of issuance of the letter, FDA would make the 
letter and the applicant's response public, after appropriate redaction 
to protect any trade secret or confidential commercial information. FDA 
would not make the letter and the applicant's response public if FDA 
determines, based on the applicant's response, that the applicant had a 
reasonable basis for not notifying FDA as required.

IV. Legal Authority

    FDA is amending its regulations to implement sections 506C and 506E 
of the FD&C Act (21 U.S.C. 356c and 356e) as amended by FDASIA. FDA's 
authority for this rule also derives from section 701(a) of the FD&C 
Act (21 U.S.C. 371(a)).

V. Analysis of Impacts

A. Introduction

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4). Executive Orders 12866 and 13563 direct Agencies to assess all 
costs and benefits of available regulatory alternatives and, when 
regulation is necessary, to select regulatory approaches that maximize 
net benefits (including potential economic, environmental, public 
health and safety, and other advantages; distributive impacts; and 
equity). OMB has determined that this proposed rule may be an 
economically significant regulatory action as defined by Executive 
Order 12866.
    The Regulatory Flexibility Act requires Agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. The estimated per notification cost for small 
business entities, $224, represents a small percentage of average 
annual sales (up to 0.10 percent), for all entities covered by the 
proposed rule. Although the final rule does not require specific 
mitigation strategies, for firms that choose to implement mitigation or 
prevention strategies, there could be additional costs of $112,000 
associated with labor resources. For pharmaceutical companies with 
fewer than 20 workers, these could be 2 to 7.8 percent of average 
annual sales. In FDA's experience, 4-5 small business entities per year 
have been affected by a shortage. For these companies, the average 
annual sales was $17.54 million, and the estimated costs of 
implementing mitigation or prevention strategies would represent less 
than 0.64 percent of their average annual sales. The Agency anticipates 
that the proposed rule will not have a significant economic impact on a 
substantial number of small entities, and seeks comments on its Initial 
Regulatory Flexibility Analysis.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that Agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $141 million, using the most current (2012) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
proposed rule to result in any 1-year expenditure that would meet or 
exceed this amount.

B. Summary

    The proposed rule would amend FDA's regulations to implement 
sections 506C and 506E of the FD&C Act, as amended by FDASIA. The 
proposed rule would require all applicants of covered, approved drugs 
or biological products other than blood or blood components, all 
applicants of blood or blood components that manufacture a significant 
percentage of the U.S. blood supply, and all manufacturers of covered 
drugs marketed without an approved application, to notify FDA 
electronically of a permanent discontinuance or an interruption in 
manufacturing of the product that is likely to lead to a meaningful 
disruption in supply (or a significant disruption for blood or blood 
components) of the product in the United States. Notification would be 
required 6 months in advance of the permanent discontinuance or 
interruption in manufacturing, or, if that is not possible, as soon as 
practicable. The proposed rule also describes how to submit such a 
notification, the information required to be included in such a 
notification, the consequences for failure to submit a required 
notification, the disclosure of shortage-related information, and the 
meaning of certain terms.
    The proposed rule would impose annual costs of up to $39.34 million 
on those applicants or entities affected by

[[Page 65918]]

the rule, and up to $8.29 million on FDA associated with reporting and 
undertaking mitigation strategies. Estimated total annual costs of the 
interactions between industry and FDA range between $14.99 million and 
$47.62 million. Discounting over 20 years, annual quantified benefits 
from avoiding the purchase of alternative products, managing product 
shortages, and life-years gained, would range from $27.56 million to 
$86.77 million using a 3 percent discount rate, and from $27.50 million 
to $86.61 million using a 7 percent discount rate. Annualized over 20 
years, net benefits range from $12.57 million to $39.15 million using a 
3 percent discount rate, and from $12.51 million to $38.99 million 
using a 7 percent discount rate. The public health benefits, mostly 
nonquantified, include the value of information that would assist FDA, 
manufacturers, health care providers, and patients in evaluating, 
mitigating, and preventing shortages of drugs and biological products 
that could otherwise result in non-fatal adverse events, errors, 
delayed patient treatment, or interruption in clinical trial 
development. The costs and benefits are summarized in table 2. Under 
the current environment all notifications provide meaningful 
information to identify a shortage or to prevent one, but there is 
uncertainty as to whether the scope of the proposed rule could result 
in notifications that do not provide information about any shortage and 
lead to additional costs. FDA seeks comments on this issue.
    The full discussion of economic impacts is available in docket FDA-
2011-N-0898 and at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm (Ref. 3 of this proposed rule).

                                     Table 2--Summary of Benefits, Costs and Distributional Effects of Proposed Rule
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                 Primary      Low        High       Year     Discount    Period
                   Category                      estimate   estimate   estimate   dollars      rate     covered                    Notes
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                        Benefits
--------------------------------------------------------------------------------------------------------------------------------------------------------
Annualized Monetized (millions $/year)........    $57.165    $27.556    $86.773       2012         3%    2014-33  There is uncertainty surrounding these
                                                  $57.055    $27.501    $86.609       2012         7%    2014-33   estimates since some underlying
                                                                                                                   estimates came from non-
                                                                                                                   representative studies.
Annualized Quantified.........................  .........  .........  .........  .........         3%    2014-33  20-63 preventable shortages per year.
                                                                                                   7%    2014-33
                                               ---------------------------------------------------------------------------------------------------------
Qualitative...................................  Reduction in errors and non-fatal adverse events associated with shortages. Uninterrupted patient access
                                                to drugs and biological products necessary for treatment; continued access to drugs used in clinical
                                                trial development.
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                          Costs
--------------------------------------------------------------------------------------------------------------------------------------------------------
Annualized Monetized (millions $/year)........    $31.306    $14.990    $47.621       2012         3%    2014-33  There is uncertainty about potential
                                                  $31.306    $14.990    $47.621       2012         7%    2014-33   noise from notifications that might
                                                                                                                   not provide meaningful information,
                                                                                                                   but which could result in additional
                                                                                                                   review costs. In addition, these
                                                                                                                   estimates assume that applicants will
                                                                                                                   participate in mitigation or
                                                                                                                   preventive strategies.
                                               ---------------------------------------------------------------------------------------------------------
Annualized Quantified.........................  None estimated.
                                               ---------------------------------------------------------------------------------------------------------
Qualitative...................................  None estimated.
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                        Transfers
--------------------------------------------------------------------------------------------------------------------------------------------------------
Federal Annualized Monetized (millions $/year)  None estimated.
                                               ---------------------------------------------------------------------------------------------------------
Other Annualized Monetized (millions $/year)..  None estimated.
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                         Effects
--------------------------------------------------------------------------------------------------------------------------------------------------------
State, Local or Tribal Gov't..................  None.
                                               ---------------------------------------------------------------------------------------------------------
Small Business................................  FDA anticipates that when finalized, small business entities covered by the proposed rule will incur
                                                small costs, $224 per notification or up to 0.10 percent of their average annual sales. Although the
                                                proposed rule would not require it, some firms may choose to incur additional costs associated with
                                                mitigation or prevention strategies.
                                               ---------------------------------------------------------------------------------------------------------
Wages.........................................  No estimated effect.
                                               ---------------------------------------------------------------------------------------------------------
Growth........................................  No estimated effect.
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 65919]]

VI. Paperwork Reduction Act of 1995

    This proposed rule contains collections of information that are 
subject to review by the Office of Management and Budget (OMB) under 
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520) (the PRA). A 
description of these provisions is given below with an annual reporting 
burden. Included in the estimate is the time for reviewing 
instructions, searching existing data sources, gathering and 
maintaining the data needed, and completing and reviewing the 
collection of information.
    FDA invites comments on: (1) Whether the proposed collection of 
information is necessary for proper performance of FDA's functions, 
including whether the information will have practical utility; (2) the 
accuracy of FDA's estimate of the burden of the proposed collection of 
information, including the validity of the methodology and assumptions 
used; (3) ways to enhance the quality, utility, and clarity of the 
information to be collected; and (4) ways to minimize the burden of the 
collection of information on respondents, including through the use of 
automated collection techniques, when appropriate, and other forms of 
information technology.
    Title: Permanent Discontinuance or Interruption in Manufacturing of 
Certain Drug or Biological Products; Proposed Rule
    Description: Under the proposed rule, applicants with an approved 
NDA or ANDA for a covered drug product, manufacturers of a covered drug 
product marketed without an approved application, and applicants with 
an approved BLA for a covered biological product (including certain 
applications of blood or blood components) would be required to notify 
FDA in writing of a permanent discontinuance of the manufacture of the 
drug or biological product or an interruption in manufacturing of the 
drug or biological product that is likely to lead to a meaningful 
disruption in the applicant's supply (or a significant disruption for 
blood or blood components) of that product. The notification would be 
required if the drug or biological product is life supporting, life 
sustaining, or intended for use in the prevention or treatment of a 
debilitating disease or condition, including use in emergency medical 
care or during surgery, and if the drug or biological product is not a 
radiopharmaceutical drug product.
    The proposed rule would require the notification to include the 
following information: (1) The name of the drug or biological product 
subject to the notification, including the NDC (or, for a biological 
product that does not have an NDC, an alternative standard for 
identification and labeling that has been recognized as acceptable by 
the Center Director); (2) the name of each applicant of the drug or 
biological product; (3) whether the notification relates to a permanent 
discontinuance of the drug or biological product or an interruption in 
manufacturing of the product; (4) a description of the reason for the 
permanent discontinuance or interruption in manufacturing; and (5) the 
estimated duration of the interruption in manufacturing.
    Under the proposed rule, the notification would be required to be 
submitted to FDA electronically at least 6 months prior to the date of 
the permanent discontinuance or interruption in manufacturing. If 6 
months' advance notice is not possible because the permanent 
discontinuance or interruption in manufacturing was unanticipated 6 
months in advance, the applicant would be required to notify FDA as 
soon as practicable, but in no case later than 5 business days after 
the permanent discontinuance or interruption in manufacturing occurs.
    If an applicant fails to submit the required notification, the 
proposed rule would require FDA to issue a letter informing the 
applicant or manufacturer of its noncompliance. The applicant would be 
required to submit to FDA, not later than 30 calendar days after FDA 
issues the letter, a written response setting forth the basis for 
noncompliance and providing the required notification.
    Description of Respondents: Applicants of prescription drugs and 
biological products subject to an approved NDA, ANDA, or BLA, and 
manufacturers of prescription drug products marketed without an 
approved ANDA or NDA, if the product is life supporting, life 
sustaining, or intended for use in the prevention or treatment of a 
debilitating disease or condition, including use in emergency medical 
care or during surgery, and is not a radiopharmaceutical product. If 
the BLA applicant is a manufacturer of blood or blood components, it is 
only subject to this rule if it manufactures a significant percentage 
of the nation's blood supply.
    Burden Estimates: Based on the number of drug and biological 
product shortage related notifications we have seen during the past 12 
months, we estimate that annually a total of approximately 75 
respondents (``number of respondents'' in table 3) would notify us of a 
permanent discontinuance of the manufacture of a drug or biological 
product or an interruption in manufacturing of a drug or biological 
product that is likely to lead to a meaningful disruption in the 
respondent's supply of that product under the proposed rule. We 
estimate that these respondents would submit annually a total of 
approximately 305 notifications as required under proposed Sec. Sec.  
310.306, 314.81(b)(3)(iii), and 600.82. Approximately 80 of these 
notifications are notifications that we currently receive under OMB 
control number 0910-0699 for the IFR, thus we expect to receive 
approximately 225 new notifications under the proposed rule (``total 
annual responses'' in table 3).\10\ We estimate three notifications per 
respondent, because a respondent may experience multiple 
discontinuances or interruptions in manufacturing in a year that 
require notification (``no. of responses per respondent'' in table 3). 
We also estimate that preparing and submitting these notifications to 
FDA would take approximately 2 hours per respondent (``hours per 
response'' in table 3).
---------------------------------------------------------------------------

    \10\ This estimate is based on the number of new notifications 
we would receive under the proposed rule as compared to 
notifications we currently receive under the IFR. The IFR is our 
baseline for comparison for purposes of estimating the burden under 
the PRA, because additional notifications that we may currently 
receive, but that are not required under the IFR (e.g., as requested 
in the draft guidance for industry on Notification to the Food and 
Drug Administration of Issues That May Result in a Prescription Drug 
Shortage) are not covered under any existing OMB control number, and 
thus must be captured in this PRA estimate. In contrast, the 
preliminary analysis of impacts of the proposed rule estimates the 
costs and benefits of the proposed rule as compared to current 
practice. As a result of the use of different baselines for 
comparison, the estimate of new notifications under the PRA does not 
match the estimate of new notifications included in the preliminary 
analysis of impacts (see Table 2B of Ref. 3, which estimates the 
number of new notifications we would receive under the proposed 
rule, as compared to the number of notifications the Agency receives 
currently, including all voluntary notifications not specifically 
required by the IFR).
---------------------------------------------------------------------------

    We base these estimates on our experience with the reporting of 
similar information to FDA since the issuance of the President's 
Executive Order 13588 of October 31, 2011 (Ref. 1 of this proposed 
rule), and under the interim final rule entitled ``Applications for 
Food and Drug Administration Approval To Market a New Drug; Revision of 
Postmarketing Reporting Requirements--Permanent'' (76 FR 78530; 
December 19, 2011), and the draft guidance entitled ``Draft Guidance 
for Industry on Notification to Food and Drug Administration of Issues 
That May Result in a Prescription Drug Shortage'' (77 FR 11550; 
February 27, 2012).
    FDA estimates the burden of this collection of information as 
follows:

[[Page 65920]]

                                                         Table 3--Estimated Reporting Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                         Number of
                                                                        Number of      responses per     Total annual      Hours per       Total hours
                                                                       respondents       respondent       responses         response
--------------------------------------------------------------------------------------------------------------------------------------------------------
Notifications required under proposed Sec.  Sec.   310.306                       75                3              225                2              450
 (unapproved drugs), 314.81(b)(3)(iii) (products approved under an
 NDA or ANDA), and 600.82 (products approved under a BLA)..........
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this information collection.

    The information collection provisions of this proposed rule have 
been submitted to OMB for review. Interested persons are requested to 
fax comments regarding the information collection by December 4, 2013, 
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: 202-395-7245, 
or emailed to oira_submission@omb.eop.gov. All comments should be 
identified with the title of this information collection and should 
include the FDA docket number found in brackets in the heading of this 
document.

VII. Federalism

    FDA has analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the proposed rule, if finalized, 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 tentatively concludes that the proposed rule 
does not contain policies that have federalism implications as defined 
in the Executive order and, consequently, a federalism summary impact 
statement is not required.

VIII. 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.

IX. Comments

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

X. References

    The following references have been placed on display in the 
Division of Dockets Management (see ADDRESSES) and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday, 
and are available electronically at http://www.regulations.gov. (FDA 
has verified all the Web site addresses in this reference section, but 
we are not responsible for any subsequent changes to the Web sites 
after this document publishes in the Federal Register).

1. 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 November 2012.
2. 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 November 
2012.
3. Preliminary Regulatory Impact Analysis, Initial Regulatory 
Flexibility Analysis, and Unfunded Mandates Reform Act Analysis for 
Permanent Discontinuance or Interruption in Manufacturing of Certain 
Drug or Biological Products; Proposed Rule, available at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

List of Subjects

21 CFR Part 20

    Confidential business information, Courts, Freedom of information, 
Government employees.

21 CFR Part 310

    Administrative practice and procedure, Drugs, Labeling, Medical 
devices, Reporting and recordkeeping requirements.

21 CFR Part 314

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

21 CFR Part 600

    Biologics, 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, it is proposed that 21 CFR parts 20, 
310, 314, and 600 be amended as follows:

PART 20--PUBLIC INFORMATION

0
1. The authority citation for 21 CFR part 20 continues to read as 
follows:

    Authority: 5 U.S.C. 552; 18 U.S.C. 1905; 19 U.S.C. 2531-2582; 21 
U.S.C. 321-393; 1401-1403; 42 U.S.C. 241, 242, 242a, 242l, 242n, 
243, 262, 263, 263b-263n, 264, 265, 300u-300u-5, 300aa-1.

0
2. Revise Sec.  20.100 by adding paragraph (c)(45) to read as follows:

Sec.  20.100  Applicability; cross-reference to other regulations.

* * * * *
    (c) * * *
    (45) Postmarket notifications of a permanent discontinuance or an 
interruption in manufacturing of certain drugs or biological products, 
in Sec. Sec.  310.306, 314.81(b)(3)(iii), and 600.82 of this chapter.

PART 310--NEW DRUGS

0
3. The authority citation for 21 CFR part 310 is revised to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356c, 356e, 
360b-360f, 360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 
242(a), 262, 263b-263n.

0
4. Add Sec.  310.306 to subpart D to read as follows:

[[Page 65921]]

Sec.  310.306  Notification of a permanent discontinuance or an 
interruption in manufacturing of marketed prescription drugs for human 
use without approved new drug applications.

    (a) Applicability. Marketed prescription drug products that are not 
the subject of an approved new drug or abbreviated new drug application 
are subject to this section.
    (b) Notification of a permanent discontinuance or an interruption 
in manufacturing. The manufacturer of each product subject to this 
section must make the notifications required under Sec.  
314.81(b)(3)(iii) of this chapter and otherwise comply with Sec.  
314.81(b)(3)(iii) of this chapter. If the manufacturer of a product 
subject to this section fails to provide notification as required under 
Sec.  314.81(b)(3)(iii), FDA will send a letter to the manufacturer and 
otherwise follow the procedures set forth under Sec.  
314.81(b)(3)(iii)(e).
    (c) Drug Shortages List. FDA will include on the drug shortages 
list required by Sec.  314.81(b)(3)(iii)(d) drug products that are 
subject to this section that it determines to be in shortage. For such 
drug products, FDA will provide the names of each manufacturer rather 
than the names of each applicant. With respect to information collected 
under this paragraph FDA will observe the confidentiality and 
disclosure provisions set forth in Sec.  314.81(b)(3)(iii)(d)(2).

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

0
5. The authority citation for 21 CFR part 314 is revised to read as 
follows:

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

0
6. Revise Sec.  314.81 paragraph (b)(3)(iii) to read as follows:

Sec.  314.81  Other postmarketing reports.

* * * * *
    (b) * * *
    (3) * * *
    (iii) Notification of a permanent discontinuance or an interruption 
in manufacturing.
    (a) An applicant of a prescription drug product must notify FDA in 
writing of a permanent discontinuance of manufacture of the drug 
product or an interruption in manufacturing of the drug product that is 
likely to lead to a meaningful disruption in supply of that drug in the 
United States if:
    (1) The drug product is life supporting, life sustaining, or 
intended for use in the prevention or treatment of a debilitating 
disease or condition, including any such drug used in emergency medical 
care or during surgery; and
    (2) The drug product is not a radiopharmaceutical drug product.
    (b) Notifications required by paragraph (b)(3)(iii)(a) of this 
section must be submitted to FDA electronically in a format that FDA 
can process, review, and archive:
    (1) At least 6 months prior to the date of the permanent 
discontinuance or interruption in manufacturing; or
    (2) If 6 months' advance notice is not possible because the 
permanent discontinuance or interruption in manufacturing was not 
reasonably anticipated 6 months in advance, as soon as practicable 
thereafter, but in no case later than 5 business days after the 
permanent discontinuance or interruption in manufacturing occurs.
    (c) Notifications required by paragraph (b)(3)(iii)(a) of this 
section must include the following information:
    (1) The name of the drug subject to the notification, including the 
NDC for such drug;
    (2) The name of the applicant;
    (3) Whether the notification relates to a permanent discontinuance 
of the drug or an interruption in manufacturing of the drug;
    (4) A description of the reason for the permanent discontinuance or 
interruption in manufacturing; and
    (5) The estimated duration of the interruption in manufacturing.
    (d)(1) FDA will maintain a publicly available list of drugs that 
are determined by FDA to be in shortage. This drug shortages list will 
include the following information:
    (i) The names and NDC(s) for such drugs;
    (ii) The name of each applicant for such drugs;
    (iii) The reason for the shortage, as determined by FDA from the 
following categories: Requirements related to complying with good 
manufacturing practices; regulatory delay; shortage of an active 
ingredient; shortage of an inactive ingredient component; 
discontinuation of the manufacture of the drug; delay in shipping of 
the drug; demand increase for the drug; or other reason; and
    (iv) The estimated duration of the shortage.
    (2) FDA may choose not to make information collected to implement 
this paragraph available on the drug shortages list or available under 
section 506C(c) of the FD&C Act if FDA determines that disclosure of 
such information would adversely affect the public health (such as by 
increasing the possibility of hoarding or other disruption of the 
availability of drug to patients). FDA will also not provide 
information on the public drug shortages list or under section 506C(c) 
of the FD&C Act that is protected by 18 U.S.C. 1905 or 5 U.S.C. 
552(b)(4), including trade secrets and commercial or financial 
information that is considered confidential or privileged under Sec.  
20.61.
    (e) If an applicant fails to submit a notification as required 
under paragraph (b)(3)(iii)(a) of this section and in accordance with 
paragraph (b)(3)(iii)(b) of this section, FDA will issue a letter to 
the applicant informing it of such failure.
    (1) Not later than 30 calendar days after the issuance of such a 
letter, the applicant must submit to FDA a written response setting 
forth the basis for noncompliance and providing the required 
notification under paragraph (b)(3)(iii)(a) of this section and 
including the information required under paragraph (b)(3)(iii)(c) of 
this section; and
    (2) Not later than 45 calendar days after the issuance of a letter 
under paragraph (b)(3)(iii)(e) of this section, FDA will make the 
letter and the applicant's response to the letter public, unless, after 
review of the applicant's response, FDA determines that the applicant 
had a reasonable basis for not notifying FDA as required under 
paragraph (b)(3)(iii)(a) of this section.
    (f) The following definitions of terms apply to paragraph 
(b)(3)(iii) of this section:
    Drug shortage or shortage means a period of time when the demand or 
projected demand for the drug within the United States exceeds the 
supply of the drug.
    Intended for use in the prevention or treatment of a debilitating 
disease or condition means a drug product intended for use in the 
prevention or treatment of a disease or condition associated with 
mortality or morbidity that has a substantial impact on day-to-day 
functioning.
    Life supporting or life sustaining means a drug product that is 
essential to, or that yields information that is essential to, the 
restoration or continuation of a bodily function important to the 
continuation of human life.
    Meaningful disruption means a change in production that is 
reasonably likely to lead to a reduction in the supply of a drug by a 
manufacturer that is more than negligible and affects the ability of 
the manufacturer to fill orders or meet expected demand for its 
product, and does not include interruptions in manufacturing due to 
matters such as routine maintenance or

[[Page 65922]]

insignificant changes in manufacturing so long as the manufacturer 
expects to resume operations in a short period of time.
* * * * *

Sec.  314.91  [Removed]

0
7. Remove Sec.  314.91.

PART 600--BIOLOGICAL PRODUCTS: GENERAL

0
8. The authority citation for 21 CFR part 600 is revised to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 356c, 356e, 360, 
360i, 371, 374; 42 U.S.C. 216, 262, 263, 263a, 264, 300aa-25.

0
9. Add Sec.  600.82 to subpart D to read as follows:

Sec.  600.82  Notification of a permanent discontinuance or an 
interruption in manufacturing.

    (a) Notification of a permanent discontinuance or an interruption 
in manufacturing.
    (1) An applicant of a biological product, other than blood or blood 
components for transfusion, which is licensed under section 351 of the 
Public Health Service Act, and which may be dispensed only under 
prescription under section 503(b)(1) of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 353(b)(1)), must notify FDA in writing of a 
permanent discontinuance of manufacture of the biological product or an 
interruption in manufacturing of the biological product that is likely 
to lead to a meaningful disruption in supply of that biological product 
in the United States if:
    (i) The biological product is life supporting, life sustaining, or 
intended for use in the prevention or treatment of a debilitating 
disease or condition, including any such biological product used in 
emergency medical care or during surgery; and
    (ii) The biological product is not a radiopharmaceutical biological 
product.
    (2) An applicant of blood or blood components for transfusion, 
which is licensed under section 351 of the Public Health Service Act, 
and which may be dispensed only under prescription under section 503(b) 
of the Federal Food, Drug, and Cosmetic Act, must notify FDA in writing 
of a permanent discontinuance of manufacture of any product listed in 
its license or an interruption in manufacturing of any such product 
that is likely to lead to a significant disruption in supply of that 
product in the United States if:
    (i) The product is life supporting, life sustaining, or intended 
for use in the prevention or treatment of a debilitating disease or 
condition, including any such product used in emergency medical care or 
during surgery; and
    (ii) The applicant is a manufacturer of a significant percentage of 
the U.S. blood supply.
    (b) Submission and timing of notification. Notifications required 
by paragraph (a) of this section must be submitted to FDA 
electronically in a format that FDA can process, review, and archive:
    (1) At least 6 months prior to the date of the permanent 
discontinuance or interruption in manufacturing; or
    (2) If 6 months' advance notice is not possible because the 
permanent discontinuance or interruption in manufacturing was not 
reasonably anticipated 6 months in advance, as soon as practicable 
thereafter, but in no case later than 5 business days after such a 
permanent discontinuance or interruption in manufacturing occurs.
    (c) Information included in notification. Notifications required by 
paragraph (a) of this section must include the following information:
    (1) The name of the biological product subject to the notification, 
including the National Drug Code for such biological product, or an 
alternative standard for identification and labeling that has been 
recognized as acceptable by the Center Director;
    (2) The name of the applicant of the biological product;
    (3) Whether the notification relates to a permanent discontinuance 
of the biological product or an interruption in manufacturing of the 
biological product;
    (4) A description of the reason for the permanent discontinuance or 
interruption in manufacturing; and
    (5) The estimated duration of the interruption in manufacturing.
    (d)(1) Public list of biological product shortages. FDA will 
maintain a publicly available list of biological products that are 
determined by FDA to be in shortage. This biological product shortages 
list will include the following information:
    (i) The names and National Drug Codes for such biological products, 
or the alternative standards for identification and labeling that have 
been recognized as acceptable by the Center Director;
    (ii) The name of each applicant for such biological products;
    (iii) The reason for the shortage, as determined by FDA, selecting 
from the following categories: Requirements related to complying with 
good manufacturing practices; regulatory delay; shortage of an active 
ingredient; shortage of an inactive ingredient component; 
discontinuation of the manufacture of the biological product; delay in 
shipping of the biological product; demand increase for the biological 
product; or other reason; and
    (iv) The estimated duration of the shortage.
    (2) Confidentiality. FDA may choose not to make information 
collected to implement this paragraph available on the biological 
product shortages list or available under section 506C(c) of the FD&C 
Act if FDA determines that disclosure of such information would 
adversely affect the public health (such as by increasing the 
possibility of hoarding or other disruption of the availability of the 
biological product to patients). FDA will also not provide information 
on the public shortages list or under section 506C(c) of the FD&C Act 
that is protected by 18 U.S.C. 1905 or 5 U.S.C. 552(b)(4), including 
trade secrets and commercial or financial information that is 
considered confidential or privileged under Sec.  20.61 of this 
chapter.
    (e) Noncompliance letters. If an applicant fails to submit a 
notification as required under paragraph (a) of this section and in 
accordance with paragraph (b) of this section, FDA will issue a letter 
to the applicant informing it of such failure.
    (1) Not later than 30 calendar days after the issuance of such a 
letter, the applicant must submit to FDA a written response setting 
forth the basis for noncompliance and providing the required 
notification under paragraph (a) of this section and including the 
information required under paragraph (c) of this section; and
    (2) Not later than 45 calendar days after the issuance of a letter 
under this paragraph, FDA will make the letter and the applicant's 
response to the letter public, unless, after review of the applicant's 
response, FDA determines that the applicant had a reasonable basis for 
not notifying FDA as required under paragraph (a) of this section.
    (f) Definitions. The following definitions of terms apply to this 
section:
    Biological product shortage or shortage means a period of time when 
the demand or projected demand for the biological product within the 
United States exceeds the supply of the biological product.
    Intended for use in the prevention or treatment of a debilitating 
disease or condition means a biological product intended for use in the 
prevention or treatment of a disease or condition associated with 
mortality or morbidity that has a substantial impact on day-to-day 
functioning.
    Life supporting or life sustaining means a biological product that 
is

[[Page 65923]]

essential to, or that yields information that is essential to, the 
restoration or continuation of a bodily function important to the 
continuation of human life.
    Meaningful disruption means a change in production that is 
reasonably likely to lead to a reduction in the supply of a biological 
product by a manufacturer that is more than negligible and affects the 
ability of the manufacturer to fill orders or meet expected demand for 
its product, and does not include interruptions in manufacturing due to 
matters such as routine maintenance or insignificant changes in 
manufacturing so long as the manufacturer expects to resume operations 
in a short period of time.
    Significant disruption means a change in production that is 
reasonably likely to lead to a reduction in the supply of blood or 
blood components by a manufacturer that substantially affects the 
ability of the manufacturer to fill orders or meet expected demand for 
its product, and does not include interruptions in manufacturing due to 
matters such as routine maintenance or insignificant changes in 
manufacturing so long as the manufacturer expects to resume operations 
in a short period of time.

    Dated: October 28, 2013.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2013-25956 Filed 10-31-13; 11:15 am]
BILLING CODE 4160-01-P