[Federal Register Volume 80, Number 130 (Wednesday, July 8, 2015)]
[Rules and Regulations]
[Pages 38915-38940]
[FR Doc No: 2015-16659]

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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: Final rule.

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SUMMARY: The Food and Drug Administration (FDA or the Agency) is
amending 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 rule requires 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: The rule is effective September 8, 2015.

FOR FURTHER INFORMATION CONTACT: Jouhayna Saliba, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 22, rm. 6206, Silver Spring, MD 20993, 301-796-
1300; or Stephen Ripley, Center for Biologics Evaluation and Research,
Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 71, rm.
7301, Silver Spring, MD 20993,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

Table of Contents

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

Executive Summary

Purpose of the 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 as 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 certain drug shortages provisions in
FDASIA by January 9, 2014. FDA believes this final rule will improve
FDA's ability to identify potential drug shortages and to prevent or
mitigate the impact of these shortages.

Summary of the Major Provisions of the Rule

    The rule modifies FDA's regulations to implement sections 506C and
506E of the FD&C Act as amended by FDASIA. Sections 310.306,
314.81(b)(3)(iii), and 600.82 (21 CFR 310.306, 314.81(b)(3)(iii), and
600.82) require all applicants of certain approved drugs or biological
products,\1\ including applicants of blood or blood components \2\ 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 \3\ are 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 rule requires
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 document, the term ``biological
product'' refers to a biological product licensed under section 351
of the Public Health Service Act (42 U.S.C. 262), 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)). This rule does
not apply to biological products that also meet the definition of a
device in section 201(h) of the FD&C Act.
    \2\ As used throughout this rule, the term ``blood and blood
components'' refers to blood and blood components for transfusion
other than Source Plasma, which is outside the scope of this rule.
    \3\ 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
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 rule also provides that FDA will issue a noncompliance letter
to an applicant for failure to notify FDA under the rule; specifies
minimum information that must be included in the notification; codifies
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
defines 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 rule includes a technical revision to Sec.  20.100 (21
CFR 20.100) (public disclosure regulations) to include a cross-
reference to the disclosure provisions in Sec. Sec.  310.306, 314.81,
and 600.82; and removes Sec.  314.91 related to reducing the 6-month
notification period for ``good cause,'' since it is no longer
applicable under section 506C of the FD&C Act as amended by FDASIA.

Summary of the Costs and Benefits of the Rule

    The rule imposes annual reporting costs of up to $16,827 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 $1.85 and $5.94 million,
and industry between $2.97 and $9.55 million. We also estimate annual
costs for industry between $9.57 and $30.97 million associated with
increasing production. Estimated total annual costs of the interactions
between industry and FDA range between $14.54 and $46.92 million.
Discounting over 20 years, annualized quantified benefits from avoiding
the purchase of alternative products, managing product shortages, and
life-years gained, would range from $30.45 million to $98.65 million
using a 3 percent discount rate, and from $30.39 million to $98.42
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.

I. 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 new drug shortages significantly decreased in 2012 to 117
shortages, in 2013 to 44 shortages, and stayed at 44 new shortages in
2014, drug and biological product shortages still represent an ongoing
challenge to public health.\4\ 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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    \4\ Information on product shortages can be found at http://www.fda.gov/drugs/drugsafety/drugshortages/default.htm (for products
regulated by the Center for Drug Evaluation and Research) and http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/Shortages/default.htm (for products regulated by the Center for Biologics
Evaluation and Research).
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    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 ensuring that FDA and the public receive
adequate advance notice of shortages whenever possible'' (Ref. 1). 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 and other stakeholders to successfully
prevent numerous shortages by 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 regulatory flexibility and discretion in
appropriate circumstances, if this would not cause undue risk to
patients.

FDA was able to prevent just under 200 drug and biological product
shortages in 2011, more than 280 such shortages in 2012, 170 shortages
in 2013, and 101 shortages in 2014.
    In July 2012, FDASIA amended the FD&C Act to modify existing drug
shortages requirements and to add new drug shortages provisions.
Section 506C(i) of the FD&C Act, added by FDASIA, directs FDA to adopt
a final rule to implement the drug shortages provisions. The final rule
supersedes the IFR.

II. The Proposed Rule

    In the Federal Register of November 4, 2013 (78 FR 65904), FDA
published a proposed rule to implement certain drug shortages
provisions of the FD&C Act, as amended by FDASIA.\5\ The preamble to
the proposed rule explained that 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, section 506C of the FD&C Act as amended:
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    \5\ Section 506C(i)(4) of the FD&C Act specifies that in
promulgating a regulation to implement the FD&C Act's drug shortage
provisions, FDA must issue a notice of proposed rulemaking that
includes the proposed rulemaking and provide a period of no less
than 60 days for public comment on the proposed rule.
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     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.
    The Agency proposed 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) (see 78 FR 65904).
    FDA provided 60 days for public comment on the proposed rule. Based
on the comments received and FDA's experience to date receiving
notifications, maintaining public lists of drug and biological product
shortages, and working with manufacturers and stakeholders to prevent
and mitigate drug and biological product shortages, the Agency is
finalizing the rule as proposed.

III. Description of the Final Rule

A. Persons Subject to the Rule

    Sections 310.306, 314.81(b)(3)(iii), and 600.82 require
notification to FDA of a permanent discontinuance or an interruption in
manufacturing of a covered drug or biological product. The following
persons are subject to these notification requirements:
     All applicants with an approved NDA or ANDA for a covered
drug product (Sec.  314.81(b)(3)(iii)).
     All applicants with an approved BLA for a covered
biological product, other than blood or blood components (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 (Sec.  600.82(a)(2)).
     All manufacturers of a covered drug product marketed
without an approved NDA or ANDA (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 rule requires 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 rule an
ANDA, NDA, or BLA applicant is 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 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 non-applicant entity that ensures the applicant's
compliance with this rule.
    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, the rule
applies only to applicants that are manufacturers of a ``significant
percentage of the United States blood supply.'' As described more fully
in sections III.B.2.c and III.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 unnecessarily duplicating existing systems and
without being unduly burdensome for industry. 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.\6\
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    \6\ Based on 2011 National Blood Collection and Utilization
Survey (NBCUS) data, 10 percent or more of the U.S. blood supply
would mean more than 1.5 million units of whole blood annually or
approximately 125,000 units per month. We note, however, that these
numbers may fluctuate year to year. See 2011 National Blood
Collection and Utilization Survey Report, available at http://www.hhs.gov/ash/bloodsafety/nbcus/.
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B. Products Covered by the 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 rule applies to all prescription drug products approved under
an NDA or ANDA (Sec.  314.81(b)(3)(iii)), all marketed unapproved
prescription drug products (Sec.  310.306), and all prescription
biological products approved under a BLA (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.\7\
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    \7\ 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.
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    FDASIA does not define the terms ``life supporting,'' ``life
sustaining,'' or ``intended for use in the prevention or treatment of a
debilitating disease or condition,'' but instead requires FDA to define
them (section 506C(i)(2) of the FD&C Act). Sections
314.81(b)(3)(iii)(f) and 600.82(f) define a ``life supporting or life
sustaining'' drug or biological 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.'' As explained in the preamble to the proposed rule (78 FR
65904 at 65909), 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 pre-FDASIA section 506C (72
FR 58993 at 58994, October 18, 2007), and in

medical device regulations (see 21 CFR 821.3(g)).
    The final rule defines ``intended for use in the prevention or
treatment of a debilitating disease or condition'' to mean ``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'' (Sec. Sec.  314.81(b)(3)(iii)(f) and
600.82(f)). FDA equates ``debilitating disease or condition'' with
``serious disease or condition'' under this definition, and we have
defined it according to the definition of ``serious'' found in Sec.
312.300 (21 CFR 312.300), which governs expanded access to
investigational new drugs. 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).
    It is important to note that the 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 shortages
of CDER-regulated products (CDER MAPP 4190.1 Rev. 2) (Ref. 2) and the
existing Center for Biologics Evaluation and Research (CBER) Standard
Operating Policy and Procedure (SOPP) on shortages of CBER-regulated
products (CBER SOPP 8506) (Ref. 3). In general, FDA considers a product
to be medically necessary under the internal MAPP and SOPP if there is
no other product that is judged by CDER or CBER medical staff to be an
appropriate substitute or there is an inadequate supply of an
acceptable alternative, as determined by appropriate CDER and CBER
personnel. In contrast, under this rule, an applicant is 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 or SOPP. Under the
MAPP and SOPP, FDA uses the definition of medically necessary to
prioritize the Agency's response to specific shortages or potential
shortages and to allocate resources appropriately.
2. Biological Products
    Section 506C of the FD&C Act, as amended, states that for purposes
of section 506C, 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 (HHS) (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.
    As proposed, FDA is applying 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. Shortages of
biological products can have serious negative consequences for patients
who rely on these products for their treatment. FDA anticipates that
early notification of a permanent discontinuance or an interruption in
the manufacturing of biological products will allow the Agency to
address, prevent, or mitigate a shortage of these products, greatly
benefiting the public health. In addition, we have determined that
requiring manufacturers of biological products to notify FDA under this
rule will not duplicate the existing reporting programs of which we are
aware.
    a. Plasma-derived products and their recombinant analogs. Under
Sec.  600.82(a), the requirements of section 506C of the FD&C Act apply
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). As
explained in the preamble to the proposed rule (78 FR 65904 at 65910),
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.
    FDA recognizes and greatly appreciates the efforts by PPTA to
provide plasma product supply information to FDA and the public.
However, as described in detail in the preamble to the proposed rule
(78 FR 65904 at 65910), FDA concluded that it would benefit the public
health for the Agency to receive direct notification under this rule
from all manufacturers of these products. Because the PPTA program does
not serve the same purpose as notification under this rule, including
plasma-derived products and their recombinant analogs in this rule will
not duplicate the PPTA system. FDA believes that including these
products within the scope of the 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. 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\ As
explained in the preamble to the proposed rule (78 FR 65904 at 65910),
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.
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    \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.)
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    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
has determined that including vaccines within the scope of this rule 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. The rule applies
section 506C of the FD&C Act to blood or blood components, but in a
more limited manner than for other biological products (Sec.
600.82(a)(2)). The rule requires 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. The rule is intended
to require reporting of large-scale, permanent discontinuances, or
interruptions in manufacturing of blood or blood components.
    FDA anticipates that the rule will 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.
    As explained in detail in the preamble to the proposed rule (78 FR
65904 at 65911), we are aware of two significant efforts to monitor
local and regional supplies of blood or blood components: (1) America's
Blood Centers (ABC) and the Blood Availability and Safety Information
System (BASIS) and (2) 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 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
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, whereas the rule
requires reporting.
    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's 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 Task Force
information 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 only capture short-term, day-to-day supply and
distribution information. In addition, in contrast to this 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, the reporting requirements 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 III.A and
III.C.1.
3. Scope of the Term ``Product''
    Under this rule, ``product'' refers to a specific strength, dosage
form, and 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 Sec.  314.81(b)(3)(iii), but the 100-mg strength continues to be
manufactured without delay, under the 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.

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. Sections 314.81(b)(3)(iii) and 600.82
require the applicant to report all permanent discontinuances of
covered drugs and biological products to FDA. For purposes of this
rule, we interpret 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.
    i. Drugs and biological products other than blood or blood
components. Sections 314.81(b)(3)(iii)(a) and 600.82(a)(1) 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. Sections
314.81(b)(3)(iii)(f) and 600.82(f) adopt the statutory definition of
``meaningful disruption in supply.''
    Consistent with the statutory definition of meaningful disruption,
the rule requires 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 the 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 rule does not require an
applicant to predict the market-wide impact of an interruption in its
own manufacturing, which can be difficult to accurately assess and
could lead to inconsistent interpretation of the regulation, less
accurate predictions, and under- or overreporting.
    Under the rule, reportable discontinuances or interruptions in
manufacturing of a covered drug or biological product 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 is not required, under the 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 does 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 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 the rule and the applicant must 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 the list
is not exhaustive. The rule requires that 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 be reported to FDA, even if not specifically
described in this preamble.
    ii. Blood or blood components for transfusion. Section 600.82(a)(2)
requires 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
explained in section III.A, FDA intends to consider an applicant that
manufactures 10 percent or more of the U.S. blood supply to manufacture
a significant percentage of the U.S. blood supply for purposes of this
rule.\10\ Section 600.82(f) defines ``significant disruption'' as 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.''
---------------------------------------------------------------------------

    \10\ Based on 2011 NCBUS data, this would be more than 1.5
million units of whole blood annually or approximately 125,000 units
per month. However, we note that the number may fluctuate year to
year.
---------------------------------------------------------------------------

    For purposes of the 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 1-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 whether 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 definition of ``significant disruption'' (interpreted to mean
affecting 20 percent or more of an individual applicant's supply over a
1-month period) as applied to blood or blood components, in combination
with limiting the 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 III.B.2.c of this document and in the
preamble to the proposed rule (78 FR 65904 at 65911). 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 are unlikely to be identified and corrected by the existing
ABC, BASIS, and Task Force programs. The additional limitation of the
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.
    Circumstances that trigger notification to FDA of a permanent
discontinuance or an interruption in manufacturing of blood or blood
components 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; 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 is not
required under the 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 does
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 1-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 must be reported to FDA under the final rule.
    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 rule
requires any permanent discontinuance or any interruption in
manufacturing that is likely to lead to a significant disruption (as
defined by the 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.
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 6
months' advance notice is not possible, as soon as practicable.
Consistent with the statute, Sec. Sec.  314.81(b)(3)(iii)(b) and
600.82(b) 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,
FDA expects 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 must 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 6
months in advance certain interruptions in manufacturing that are
likely to lead to a meaningful disruption. 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 rule requires that
the applicant 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 must 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 or some other catastrophic incident.
Accordingly, the 5-day provision 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 III.C.6 for further discussion of the
consequences of failure to notify FDA). Additionally, it is important
to note that an applicant that could have notified the Agency before 5
days had passed, but waited until the end of the 5-day period is in
violation of the rule. Consistent with the statutory intent, whenever
possible, applicants are 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. Sections 314.81(b)(3)(iii)(b) and
600.82(b) 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<EMAIL_ADDRESS>(for products regulated by
CDER) or<EMAIL_ADDRESS>(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.'' As
described in the preamble to the proposed rule (78 FR 65904 at 65915),
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 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 eliminates Sec.  314.91 in its entirety.
3. Contents of the Notification
    Sections 314.81(b)(3)(iii)(c) and 600.82(c) 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 requires applicants to include the minimum information listed
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 III.C.4.
We recognize that the duration of an interruption in manufacturing can
be difficult to accurately predict. Therefore 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.
    Along with the required elements of the notification, applicants
are encouraged to include any other information in the notification
that may assist the Agency in working with the applicant to resolve the
permanent discontinuance or interruption in manufacturing. This
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 followup 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 of the FD&C Act 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 rule, the ANDA, NDA, or BLA
applicant is 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 and biological product shortages lists the reason for the
shortage, choosing from the following list of categories specified in
the statute:
     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
Sec. Sec.  310.306(c), 314.81(b)(3)(iii)(d), and 600.82(d), FDA will
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 rule concerning the product in
shortage. Sections 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)). As
specified in the rule, the

shortages lists will 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.
    If FDA has received a notification under the rule for the drug or
biological product, FDA will 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. Consistent with the statute,
the Agency, not the applicant, is responsible for determining which
categorical reason best fits a particular situation. In general, FDA
intends to 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 final rule we 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 section 506C notification. This
information will also assist FDA in responding quickly to the
notification. If FDA has not received a notification under the rule,
but becomes aware of a shortage through other means, FDA intends to
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, the final rule also adds an eighth category,
entitled ``Other reason.'' The Agency intends to choose ``Other
reason'' only 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, although FDA may choose the ``Other
reason'' category, the public shortages list will 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.
    The final rule codifies, 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 (for products regulated by CDER)
and http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/Shortages/default.htm (for products regulated by CBER).
    The list of CDER-regulated products 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 Sec.
314.81(b)(3)(iii)(d)); and Date Updated (last date FDA updated the
information for that particular product). The list of CBER-regulated
products includes similar information in fields for Product Name,
Reason for Shortage, and Status.
5. Confidentiality and Disclosure
    In general, as required by sections 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. Sections
314.81(b)(3)(iii)(d) and 600.82(d), however, specify that FDA may
choose not to make information collected under the authority of the
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 provisions closely track the
statutory language in sections 506C(c) and 506E(c)(3) of the FD&C Act.
    In addition, Sec. Sec.  310.306(c), 314.81(b)(3)(iii)(d), and
600.82(d), as finalized, 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 Sec.
20.61. These provisions provide appropriate protection for commercial
and trade secret information protected by other Federal law and are
consistent with 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). The final rule
also implements a technical amendment to Sec.  20.100 to include a
cross-reference to Sec. Sec.  310.306, 314.81, and 600.82. Section
20.100 describes, by cross-reference to other regulations, the rules on
public availability of certain specific categories of information.
6. Failure To Notify
    Consistent with section 506C(f) of the FD&C Act, Sec. Sec.
310.306(b), 314.81(b)(iii)(3)(e), and 600.82(e), as finalized, provide
that FDA will 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 Sec. Sec.
314.81(b)(iii)(3)(a) and 600.82(a) within the timeframe stated in
Sec. Sec.  314.81(b)(iii)(3)(b) and 600.82(b). It is important to note
that failure to notify FDA includes 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 will issue a noncompliance
letter. 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,'' FDA will issue a noncompliance letter.
Refer to section III.C.2.a for a discussion of the required timing for
section 506C notifications.
    As required by section 506C(f) of the FD&C Act, the rule provides
the applicant with 30 calendar 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. Not later than 45 calendar
days after the date of issuance of the noncompliance letter, FDA will
make the letter and the applicant's response public, after appropriate
redaction to protect any trade secret or confidential commercial
information. FDA will 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. Comments on the Proposed Rule

    The Agency received submissions from 34 commenters, including
public health associations, pharmaceutical industry, hospital groups,
consumer

groups, and individuals. A summary of the comments contained in the
submissions received and FDA's responses follow.
    To make it easier to identify comments and our responses, the word
``Comment,'' in parentheses, appears before the comment's description,
and the word ``Response,'' in parentheses, appears before our response.
We have numbered each comment to help distinguish between different
comments. Similar comments are grouped together under the same number.
The number assigned to each comment is purely for organizational
purposes and does not signify the comment's value or importance or the
order in which comments were received.

A. Persons Subject to the Rule

    (Comment 1) One comment suggested that the notification requirement
should be extended to API manufacturers. The comment stated that API
manufacturers are further upstream in the drug development chain and
that early warning of issues at this level, before they impact
manufacturers formulating the drugs, would give FDA, other
manufacturers of the drug, and programs more time to prepare and
prevent shortages from affecting patients.
    (Response) FDA does not agree that the notification requirement
should be applied to API manufacturers. While interruptions in API
supply may lead to a meaningful disruption in supply of the finished
drug or biological product, they do not always have this effect.
Therefore, notification to FDA of disruption in API supply would be
premature and would not provide information that the Agency can take
definitive action on. FDA believes that the notification requirement,
which is derived from section 506C of the FD&C Act, generally provides
the Agency with adequate notice to allow the Agency to work with the
applicant and other stakeholders to prevent a shortage. As explained in
section III.A, however, it is important that the applicant establish a
process with any relevant contract manufacturer, API supplier, or other
non-applicant entity to ensure that the applicant complies with this
rule.
    (Comment 2) One comment requested clarification on how a blood
establishment will know if it is subject to the reporting requirements
of the rule. The comment noted that the preamble to the proposed rule
(78 FR 65904 at 65908) stated that FDA intends to consider a BLA-holder
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. The comment explained that
the National Blood Collection and Utilization Survey (NBCUS) supplies
the best data available nationally on collection and utilization of
blood in the United States, but notes that the survey is voluntary and
does not occur on an annual basis. The comment stated that it is not
possible for a BLA holder to know what percentage of the U.S. blood
supply it is collecting. Accordingly, the comment recommended that FDA
identify an annual whole blood collection number to be used as the
threshold for reporting.
    (Response) FDA declines to identify an annual whole blood
collection number to be used as a threshold for reporting because these
numbers may fluctuate year to year. Because of their coordination with
other BLA holders through the ABC, BASIS, and Task Force programs, we
believe that BLA holders will generally be aware of whether they
manufacture a significant percentage of the U.S. blood supply.
Accordingly, we do not believe there will be significant uncertainty
among BLA holders about whether they are subject to the notification
requirements. If an applicant is unsure of whether it is subject to the
notification requirements, we recommend that the applicant contact CBER
at<EMAIL_ADDRESS>    (Comment 3) One comment noted that the proposed rule did not
discuss the effect of the notification provision on product allocation
systems. The comment explained that products with inherently limited
supply have been historically put on allocation systems by
manufacturers to prioritize the allocation of these products. The
comment explained that these allocation systems help manage and track
product supplies, curb gray market distribution, and prevent price
hikes. The comment stated that section 506(D)(d) of the FD&C Act
directs FDA to establish a mechanism by which health care providers and
other third party organizations may report to the Agency evidence of a
drug shortage. The comment requested confirmation that a notification
under section 506D(d) of the FD&C Act does not extend to situations
where a receiving entity (e.g., a hospital) reaches its allocation
limits.
    (Response) The comment is beyond the scope of this rulemaking. The
final rule implements sections 506C and 506E of the FD&C Act by
amending Sec. Sec.  20.100 and 314.81(b)(3)(iii) and adding new
Sec. Sec.  310.306 and 600.82. The rule does not address section 506D
of the FD&C Act. Consistent with section 506D(d), however, we do
encourage patients, providers, pharmacists, and other non-applicants to
communicate with FDA about potential shortages or disruptions in supply
by email at<EMAIL_ADDRESS>(for products regulated by CDER)
or<EMAIL_ADDRESS>(for products regulated by CBER), so that
the Agency can take appropriate steps to address these situations.

B. Products Covered by the 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
    (Comment 4) In the preamble to the proposed rule (78 FR 65904 at
65909), FDA requested comment on the proposed definitions of ``life
supporting or life sustaining'' and ``intended for use in the
prevention or treatment of a debilitating disease or condition'' and in
particular, whether the definitions might lead to ``over-
notification.'' The majority of commenters supported the proposed
definitions and agreed that they are consistent with current
understanding of these terms. Some commenters noted that there might be
the potential for over-notification but agreed that more information,
rather than less, will enhance FDA's ability to prevent drug and
biological product shortages. One comment stated that the definitions
could lead to over-notification if they are broadly interpreted but
noted that it is difficult to predict whether over-notification will
actually occur. The comment suggested that within 1 year of
implementation of the final rule, FDA can assess whether
overnotification has occurred and can revise the draft guidance for
industry entitled ``Notification to FDA of Issues that May Result in a
Prescription Drug or Biological Product Shortage'' to include
additional examples of products that are or are not likely to fall
within the scope of products subject to the notification provision.
    (Response) FDA appreciates the commenters' input. We continue to
believe that the proposed definitions provide sufficient clarity
without overly restricting the categories of products subject to the
rule. We have therefore finalized the definitions that were proposed
and believe that these definitions will result in appropriate
notifications under the rule. If, however, FDA finds that over-
notification has occurred, the Agency may consider further
clarification in guidance or by other suitable means.

    (Comment 5) Three comments stated that the proposed definitions
were overly broad, potentially encompassing the majority of approved
drug and biological products, and may be subject to inconsistent
interpretation. Two comments recommended using definitions based on the
definitions of ``immediately life-threatening disease or condition''
and ``serious disease or condition'' in Sec.  312.300. One of those
comments specifically proposed the following definitions:
     ``A life supporting or life sustaining drug product means
a drug product that is essential to, or yields information that is
essential to, the restoration or continuation of a bodily function
associated with a stage of disease in which there is a reasonable
likelihood that death will occur within a matter of months or in which
premature death is likely without early treatment.''
    and
     ``A debilitating disease or condition means a serious
disease or condition associated with morbidity that has a substantial
impact on day-to-day functioning. Short-lived and self-limiting
morbidity will usually not be sufficient, but the morbidity need not be
irreversible, provided it is persistent or recurrent. Whether a disease
or condition is serious is a matter of clinical judgment, based on its
impact on such factors as survival, day-to-day functioning, or the
likelihood that the disease, if left untreated, will progress from a
less severe condition to a more serious one.''
    (Response) FDA does not believe it is appropriate to incorporate
the comment's proposed definitions or alternative definitions based on
the definitions set forth in Sec.  312.300. As explained in section
III.B.1, under Sec. Sec.  314.81(b)(3)(iii)(f) and 600.82(f) of this
final rule, FDA equates ``debilitating disease or condition'' with
``serious disease or condition,'' and we have defined ``debilitating
disease or condition'' according to the definition of ``serious disease
or condition'' found in Sec.  312.300. In the Agency's view, the
definitions suggested in the comment would be too restrictive and could
exclude certain products, such as anesthetic products, that are
critical to patient care and should appropriately be considered ``life
supporting or life sustaining'' or ``intended for use in the prevention
or treatment of a debilitating disease or condition.'' As noted in the
previous response, FDA believes that the definitions in this final rule
provide sufficient clarity without overly restricting the categories of
products subject to the rule. If, following implementation of the rule,
it appears that further clarification is necessary, FDA will consider
what type of clarification may be beneficial and take appropriate
steps.
    (Comment 6) Three comments suggested that FDA should consider
providing a list, in guidance or otherwise, of examples of drug
products or classes of drug products that are likely to meet the
definitions of ``life supporting or life sustaining'' or ``intended for
use in the prevention or treatment of a debilitating disease or
condition.'' The commenters suggested that such a list would provide
greater clarity and facilitate compliance with the rule.
    (Response) FDA does not believe it is appropriate to provide a list
of products that are likely to meet the definitions of ``life
supporting or life sustaining'' or ``intended for use in the prevention
or treatment of a debilitating disease or condition.'' Such a list
would be difficult to maintain and keep up to date as products come off
the market and new products enter the market. We are also concerned
that applicants and the public may misinterpret the list as an
exhaustive list of all products that would be subject to the
notification requirement, rather than as examples of drug products or
classes of drug products that are likely to meet the definitions.
    If an applicant is uncertain whether a particular discontinuance or
interruption in manufacturing of a drug or biological product should be
reported to FDA, we encourage the applicant to proceed with
notification. It is important to note that, under section 1001(b) of
FDASIA, submission of a notification will not be construed as: (1) An
admission that any product that is the subject of the notification
violates any provision of the FD&C Act or (2) evidence of an intention
to promote or market the product for an unapproved use or indication.
    (Comment 7) One comment requested that FDA recognize attention-
deficit hyperactivity disorder (ADHD) as an example of a debilitating
condition. The comment stated that FDA could do so by adding to the
definition in the final rule a list of some debilitating diseases and
conditions and including ADHD in that list.
    (Response) FDA has recognized ADHD as an example of a debilitating
condition. We note further that when products used to treat ADHD have
gone into shortage, they have been included on FDA's drug shortages Web
site. However, FDA declines to add a list of examples of debilitating
conditions to the rule.
    (Comment 8) One comment requested clarification that drugs used to
treat a ``debilitating disease or condition'' include sedatives,
anesthetics, analgesics, and anti-inflammatory drugs.
    (Response) FDA has considered sedatives, anesthetics, analgesics,
and anti-inflammatory drugs to be drugs that are intended for use in
the prevention or treatment of a debilitating disease or condition.
    (Comment 9) One comment suggested that the rule be modified to give
FDA the option of including a statement in the approval letter for new
NDAs, ANDAs, or BLAs indicating that the product is covered by the
rule. The comment noted that this type of statement about the product's
status would provide clarity and could be beneficial, especially to
applicants entering the U.S. market for the first time.
    (Response) FDA understands that including a statement in the
approval letter that the product is covered by this rule would clarify
that particular product's status. The Agency is concerned, however,
that such action may create confusion about the status of other
already-approved products where the approval letter does not include a
statement regarding notification under this rule. Applicants and other
stakeholders may believe that the notification requirement only applies
with respect to products whose approval letter contains a statement
about notification under this rule. Therefore, FDA does not think it
would be appropriate to add a provision to the rule as suggested by the
comment.
    (Comment 10) One comment requested clarification that the
definition of ``medically necessary'' in the drug shortage MAPP solely
relates to the allocation of internal Agency staffing and resources and
that it has no bearing on the scope of products subject to notification
under the proposed rule or FDA's determination of an actual shortage
and public notification of a shortage.
    (Response) As explained in section IV.B.1 of this document and in
the preamble to the proposed rule, under this rule, an applicant is
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.
    (Comment 11) One comment expressed support for the inclusion of
prescription drug products marketed without an approved NDA or ANDA and
noted that such products are often critical to patient care.
    (Response) FDA agrees that prescription drug products marketed
without approved applications are important in patient care and
accordingly Sec.  310.306 is being finalized as proposed to ensure that
the Agency is notified of a permanent discontinuance or an interruption
in manufacturing of such products, as appropriate.
    (Comment 12) Three comments raised questions about off-label uses.
One comment requested clarification that off-label indications are not
included within the scope of ``marketed unapproved prescription
drugs.'' Two comments noted that many prescription drug products used
to treat children and nearly all prescription drug products used to
treat neonates are not labeled for use in those populations.
Accordingly, those two comments stated that the rule should require
notification based on off-label uses in addition to the uses in the
labeling.
    (Response) Off-label uses of drug and biological products are not
included within the scope of ``marketed unapproved prescription
drugs.'' FDA is not requiring applicants to consider off-label uses
when determining whether a product is a covered product for purposes of
the notification requirement in section 506C of the FD&C Act and
implemented in this rule. The Agency understands that off-label uses
can, in certain circumstances, be an important part of patient care. In
fact, as explained in the MAPP on drug shortages (CDER MAPP 4190.1 Rev.
2), FDA considers off-label uses when classifying products as medically
necessary for purposes of prioritization. However, off-label uses are
based on a practitioner's professional judgment about what will benefit
an individual patient, and we do not believe it would be reasonable to
expect applicants to take account of individual practitioners'
therapeutic decisionmaking in assessing whether their products are
subject to the notification requirement. We note that in many cases,
though, products that would be covered by the rule if it applied based
on an off-label use may nevertheless be covered products based on a
labeled use, in which case the applicant would be subject to the
notification requirement for that product.
2. Biological Products
    (Comment 13) Many comments strongly supported applying section 506C
of the FD&C Act to biological products. These comments expressed the
view that early notification of a permanent discontinuance or an
interruption in manufacturing of biological products would benefit the
public health by facilitating prompt action on FDA's part to address,
prevent, or mitigate a shortage of these products.
    (Response) FDA appreciates these comments and agrees that extending
the notification requirement to biological products will benefit the
public health. Therefore, consistent with section 506C(i)(3), the
Agency is finalizing Sec.  600.82 as proposed.
    (Comment 14) Two comments requested that the Agency make clear that
biosimilars are subject to the provisions of section 506C of the FD&C
Act. The comments stated that while the approval process for
biosimilars is still under development, it is important that such
products be included in the requirements of the final rule.
    (Response) This rule applies to prescription biological products
licensed under section 351 of the PHS Act,\11\ including prescription
biosimilar biological products licensed under section 351(k) of the PHS
Act, 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 excluding radiopharmaceutical products.
---------------------------------------------------------------------------

    \11\ As noted in footnote 1 to the Executive Summary, the term
``biological product'' refers to a biological product licensed under
section 351 of the PHS Act, other than a biological product that
also meets the definition of a device in section 201(h) of the FD&C
Act.
---------------------------------------------------------------------------

    (Comment 15) One comment expressed support for the inclusion of
blood or blood components for transfusion but requested clarification
on how FDA will determine which blood or blood components would be
exempt from the rule and how FDA plans to address shortages of products
determined to be exempt. In particular, the comment sought
clarification on whether the rule would apply to reagents used to
cross-match platelets for transfusion. The comment stated that there
have been shortages of these reagents recently, which has impacted
patient care.
    (Response) As explained in section III.B.2.c, the notification
requirement applies only to applicants of blood or blood components for
transfusion that manufacture a significant percentage of the U.S. blood
supply, and only when there is 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 noted in footnote 1 in the Executive Summary, the rule
does not apply to biological products that meet the definition of a
device in section 201(h) of the FD&C Act. Accordingly, this rule does
not apply to reagents or other products that CBER regulates as devices,
such as products intended for screening or confirmatory clinical
laboratory testing associated with blood banking practices and other
testing procedures (e.g., blood typing and compatibility testing).
    (Comment 16) Two comments stated that blood and blood components
should not be included in the rule. The comments cited the current
systems described in the preamble to the proposed rule (78 FR 65904 at
65911) that monitor local and regional supplies of blood or blood
components and coordinate during domestic disasters. The comments noted
that blood and blood components do not have a history of shortages and
stated that given the existing reporting systems and acknowledged
successful record of planning activities in the blood community,
coordination among the major blood organizations, and cooperation with
FDA and HHS during and following disasters, it is not necessary to add
another layer of reporting that is unlikely to provide additional
security.
    (Response) As explained in the preamble to the proposed rule (75 FR
65904 at 65911) and in section III.B.2.c, FDA agrees that the
information available from ABC and BASIS and the efforts by the Task
Force are critical to public health, and the Agency appreciates the
willingness of applicants to coordinate. However, there are limitations
to these existing systems. These systems are voluntary, they do not
result in a direct notification from an applicant to FDA, and they only
capture short-term, day-to-day supply and distribution information. In
addition, the existing systems are not equipped to predict large-scale,
significant disruptions of blood or blood components. We believe that
including blood and blood components in the final rule will allow FDA
to anticipate large-scale, significant disruptions of blood or blood
components and take appropriate action. Accordingly, FDA has determined
that including blood and blood components within the scope of this rule
will benefit the public health

by ensuring that the Agency is provided with information essential to
FDA's efforts to address shortages of these products without
duplicating existing programs.
    (Comment 17) One comment stated that cellular and gene therapy
products should not be included in the rule. The comment stated these
are relatively new products and that the notification requirements are
not necessary for them. The comment noted that BLA holders should be
reporting to FDA, at least annually, what products are being
manufactured under the license, and if an applicant is experiencing
difficulty manufacturing a product, the applicant can communicate with
FDA. The comment stated further that it is difficult to understand the
``meaningful'' process FDA would initiate if a report is received from
a cellular or gene therapy manufacturer, and recommended that if
cellular and gene therapy products are included in the final rule, FDA
should provide a specific guidance document addressing these products.
    (Response) FDA does not agree that cellular and gene therapy
products should be excluded from the rule, nor do we agree that
periodic distribution reporting or voluntary communication with FDA
regarding manufacturing difficulties are adequate to allow the Agency
to address shortages of cellular and gene therapy products. Shortages
of biological products can have serious health consequences for
patients who rely on these products for their treatment. Early
notification of a permanent discontinuance or an interruption in the
manufacturing of biological products is crucial for allowing FDA to
take steps to prevent, or mitigate a shortage of these products.
    The required distribution reports referred to in the comment do not
provide sufficient notice for FDA to anticipate a shortage or take
appropriate action to address a shortage. As explained in the preamble
to the proposed rule (78 FR 65904 at 65911), under Sec.  600.81,
applicants are required to submit to CBER or CDER information about the
quantity of product distributed under the license, including the
quantity of product distributed to distributors. As part of the 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, 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. In addition, any
distribution data received from the applicant at 6-month intervals may
not be current. Accordingly, FDA has determined that including cellular
and gene therapy products within the scope of this rule would benefit
the public health by ensuring that FDA is provided with information
that is essential to Agency's efforts to address shortages of these
products. If, following implementation of the rule, it appears that
guidance or further clarification is necessary for cellular and gene
therapy products, FDA will consider what type of guidance may be
beneficial and take appropriate steps in accordance with good guidance
practices set out in 21 CFR 10.115.
    (Comment 18) Two comments recommended that the rule not be applied
to vaccines. The comments stated that, in response to the unique nature
of vaccines, the CDC has successfully partnered with vaccine applicants
to reduce, if not eliminate completely, impacts to public health that
may arise due to a supply shortage. The comments stated that CDC
continues to be in the best position to monitor and manage vaccine
supply. The comments suggested that the CDC should continue to act as a
confidential facilitator of critical supply information that is
provided by applicants or manufacturers, to maintain these data as
proprietary and confidential, and to allow CDC to use the information
so that other applicants or manufacturers can fill the gap in the event
of an imminent shortage. In addition, the comments noted that, for over
a decade, the vaccine industry has voluntarily strived to provide FDA
with the requested minimum 6-month notice when making a determination
to discontinue production of a particular vaccine, where such a
decision was foreseeable.
    Alternatively, the comments proposed that FDA consider limiting the
scope of the proposed rule to cover only non-VFC vaccines since there
already are effective notification and distribution systems in place
under the VFC program. The comments noted that CDC maintains a
stockpile of VFC vaccines as part of its vaccine shortage notification
program. Due to the CDC's regular collaboration with vaccine
manufacturers, this program has proven highly successful in mitigating
or completely eliminating supply disruptions.
    (Response) FDA does not agree with the commenters' suggestion that
the rule should not apply to vaccines or, in the alternative, should
only apply to non-VFC vaccines. 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. FDA does
not intend this rule to disrupt the contractual process and procedures
that exist between manufacturers and CDC. However, as explained in the
preamble to the proposed rule (78 FR 65904 at 65910), approximately 30
percent of vaccines licensed in the United States are not subject to
CDC notification, including vaccines for rabies, yellow fever, and
typhoid. Even for the vaccines that are subject to CDC notification,
the information collected by CDC is not adequate for purposes of this
rule. 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 prevention
of drug and biological product shortages. Although FDA and its HHS
partners work together on vaccine supply issues, FDA believes that
including vaccines within the scope of this rule is essential to fully
support FDA's efforts to identify, address, prevent, or mitigate a
vaccine shortage.
    (Comment 19) Two comments noted that by design, influenza vaccine
is a seasonal product and consequently, is unavailable for a
significant portion of each year. The comments stated that for this
reason, both seasonal influenza and pandemic influenza vaccines should
not be covered by the rule.
    (Response) We acknowledge that some vaccines, such as those for
influenza, are seasonal products by design and consequently may be
unavailable for a significant portion of the year. It is important to
note that ``meaningful disruption'' is defined as a ``reduction in the
supply of a drug . . . that is more than negligible and affects the
ability of the manufacturer to fill orders or meet expected demand for
its product.'' In the case of a seasonal product, we anticipate that
demand would decrease during the off-season; therefore, we would not
expect that an interruption in manufacture of a seasonal product would
be likely to lead to a meaningful disruption in the off-season.
Accordingly, we decline to exempt vaccines intended for seasonal and
pandemic use. We believe shortages of biological products, including
seasonal influenza vaccines, can have serious health consequences for
patients who rely on these products. Early notification of a permanent
discontinuance or an interruption in the

manufacturing of these products will allow FDA to promptly take steps
to prevent or mitigate a shortage of these products that could
otherwise result in delayed patient access.
3. Scope of the Term ``Product''
    (Comment 20) Two comments noted that the proposed rule would apply
individually to all strengths, dosage forms, or routes of
administration for a given product regardless of the supply status for
other presentations and dosages of the same product. The commenters
suggested that the rule should allow greater flexibility and should not
apply to a product if an alternate presentation of the same therapeutic
product is available.\12\
---------------------------------------------------------------------------

    \12\ We understand the comment to mean that the rule should not
apply to a particular applicant if that applicant has available the
same product in a different presentation, e.g., a different
strength.
---------------------------------------------------------------------------

    (Response) FDA does not agree. As we explained in the preamble to
the proposed rule (78 FR 65904 at 65912), we understand that the
permanent discontinuance or interruption in manufacturing of a specific
strength, dosage form, or route of administration can have a
significant impact on the targeted needs of particular patients. The
Agency strives to ensure the availability of appropriate treatment
options for patients. We also note that 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,
thereby exacerbating difficulties in obtaining the product.
Furthermore, as explained in other comments on the proposed rule
(available in Docket No. FDA-2011-N-0898), requiring notification based
on the status of each strength, dosage form, and route of
administration helps to ensure that patients and their health care
providers have the most accurate information about potential shortages,
and can make treatment decisions accordingly.
    If the applicant has available an alternate presentation of the
same product, the applicant should include that information in the
notification as a proposal to mitigate the shortage.
    (Comment 21) One comment requested confirmation that notification
is not required when there is a shortage of a particular ``count'' of
product but overall the quantity of that product is not in shortage
(e.g., a manufacturer is in short supply of a 50-count bottle of 10-mg
pills, but there are sufficient numbers of 25-count bottles of 10-mg
pills to meet patient need).
    (Response) FDA would not require notification in the situation
described in the example provided.

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

1. Notification
    (Comment 22) One comment expressed concern about the notification
requirement as applied to blood or blood components. The comment cited
the proposed rule (78 FR 65904 at 65913) and stated that monthly
reporting of a decrease in any blood component produced by an affected
BLA holder is overly burdensome and would result in reports that are
meaningless. The comment recommended that FDA provide information and
recommendations in a draft guidance to more fully explain the goals of
this particular data collection.
    (Response) The rule requires the notification of a permanent
discontinuance or an interruption in manufacturing of blood or blood
components that is likely to lead to a significant disruption in supply
of the product in the United States. 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 1-month period to ``substantially affect'' the ability of the
applicant to fill orders or meet expected demand. Such an interruption
would be considered a significant disruption in supply. The rule does
not require manufacturers to submit or report monthly data. The rule,
as applied to BLA holders for blood or blood components for
transfusion, is intended to capture events that are likely to
precipitate large-scale disruptions in an applicant's blood supply.
    (Comment 23) One comment expressed concern that the requirement
that applicants report an ``interruption in manufacturing'' that is
likely to cause a disruption in the manufacturer's own supply of a drug
or biological product could keep important information from being
reported to FDA. The comment explained that a manufacturer that is not
experiencing ``an interruption in manufacturing,'' but rather is
experiencing a lack of available product due to an increase in demand
would not be required to notify the Agency. The comment suggested that
FDA consider expanding the notification requirement to include those
applicants experiencing a shortage in supply due to an increase in
product demand.
    (Response) FDA agrees that notification by an applicant lacking
available product because of an increase in demand, and not because of
an interruption in manufacturing, could be helpful in anticipating and
addressing potential shortages. However, such a notification
requirement is beyond the scope of section 506C of the FD&C Act
implemented by the final rule. FDA does encourage applicants to
communicate with FDA if there is an increase in demand that the
applicant is not able to meet. We also note that if an applicant
experiences an increase in demand because of another applicant's
permanent discontinuance or interruption in manufacturing, FDA would
expect to receive notification about the situation from the applicant
that has experienced the discontinuance or interruption.
    (Comment 24) Two comments recommended specific modifications to the
definition of ``meaningful disruption,'' believing it to be unclear and
potentially subject to inconsistent interpretation. First, the comments
stated that terms within the definition, such as ``reasonably likely,''
``more than negligible,'' and ``short period'' are insufficiently
precise and recommended that the terms be removed from the definition.
Second, the comments stated that, under the definition, applicants
would be required to notify FDA if any products are under allocation or
the demand for the product exceeds the available supply. Accordingly,
the comments suggested adding language to the definition with the
clarification that ``meaningful disruption'' means that the adverse
impact to supply is unable to be remediated or minimized through
allocation or other means of prioritization. Last, the comments noted
that many factors could potentially affect the ability of applicants to
fill orders, including some that are not within an applicant's control.
The comments noted that applicants do not ultimately determine, nor can
they in all cases accurately predict, volumes of orders or product
demand. One of the comments accordingly recommended that FDA consider
including language to clarify that the definition of ``meaningful
disruption'' is intended to reflect situations in which the
availability of a product to patients would be impacted. The comment
suggested that the rule should clarify whose orders the applicant needs
to be able to fill, in order to distinguish between the temporary
inability to fulfill an order to a wholesaler, as opposed to the
inability of a patient to obtain a prescription or receive appropriate
therapy.
    (Response) The final rule is being issued to implement sections
506C and 506E of the FD&C Act, consistent with section 506C(i). Section
506C(h) defines ``meaningful disruption'' as ``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 that ``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.'' The final rule adopts the statutory definition. In our view,
the language used in the statute provides flexibility to accommodate
the wide variety of circumstances that may result in drug or biological
product shortages. If there is any uncertainty about whether a
particular circumstance must be reported to FDA under the rule, we
encourage applicants to submit a notification. Early notification is
FDA's best tool for addressing shortages. Moreover, submission of a
notification will not be construed as: (1) An admission that any
product that is the subject of the notification violates any provision
of the FD&C Act or (2) as evidence of an intention to promote or market
the product for an unapproved use or indication.
    (Comment 25) One comment noted that the preamble to the proposed
rule (78 FR 65904 at 65912 and 65913) provides a number of examples of
reportable discontinuances or interruptions in manufacturing of a
covered drug or biological product. The comment stated that not all of
the examples would result in a shortage of product to patients and may
result in industry ``over-reporting'' events to the Agency.
Accordingly, the comment requested that FDA further clarify the
requisite link between the examples provided and an actual ``meaningful
disruption'' in supply.
    (Response) The list of examples provided in the preamble to the
proposed rule are intended to assist applicants in understanding what
must be reported under section 506C of the FD&C Act. As implemented by
the final rule, section 506C requires that applicants notify FDA of a
permanent discontinuance in the manufacture of a covered drug or
biological product or an interruption of the manufacture of the drug or
biological product that is likely to lead to a meaningful disruption in
the supply of that product in the United States, and the reasons for
such discontinuance or interruption. The list of examples is not
intended to include only situations that will necessarily result in a
meaningful disruption in supply. The list includes examples of events
(i.e., permanent discontinuance and interruption in manufacturing) that
are likely to lead to a meaningful disruption in supply and therefore
must be reported to the Agency.
    (Comment 26) One comment suggested that FDA amend the rule to
require blood component manufacturers to report a decrease in donations
when it is due to their own decision to close donation sites versus the
natural ebb and flow of blood donation cycles. The comment stated that
companies have the ability to create shortages with the purpose of
increasing prices by closing donation sites.
    (Response) FDA does not agree the suggested change is necessary or
appropriate. As explained in the preamble to the proposed rule (78 FR
65904 at 65913), FDA need not 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
1-month period. We expect that this type of situation would be
identified and resolved through the existing programs that coordinate
local and regional supplies of blood or blood components (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
this rule.
    (Comment 27) One comment noted that some of the quality issues
subject to notification under the rule also would be subject to
reporting under Field Alert Reports for drugs and Biological Product
Deviation Reports for biological products. In an effort to avoid dual
reporting requirements, the comment suggested that FDA attempt to
coordinate these reports and the Agency's followup in order to minimize
the burden on both FDA and applicants.
    (Response) FDA recognizes that some quality issues that result in
interruptions in manufacturing subject to this rule could also be
subject to reporting under Field Alert Reports (FARs) for drugs and
Biological Product Deviation Reports (BPDRs) for biological products.
However, FARs and BPDRs are not supply reporting programs and do not
serve the same purpose as notification under this rule. Applicants with
approved NDAs and ANDAs are required to submit FARs to FDA if they find
any significant problems with an approved drug; the purpose of the
Field Alert Program is to quickly identify drug products that pose
potential safety threats. Similarly, BPDRs are used by biological
product manufacturers to report biological product deviations that may
affect the safety, purity, or potency of a distributed product.
Problems reported through FARs and BPDRs may not lead to a shortage.
Moreover, we note that the timing of these reports and the information
provided in them may not be adequate for FDA to address potential
shortages. Therefore, we have determined that requiring manufacturers
of drugs and biological products to notify FDA under this rule will not
duplicate existing reporting programs and will provide the Agency with
necessary information and lead time to take appropriate action to
prevent or mitigate a shortage.
    (Comment 28) One comment proposed that additional factors be taken
into consideration and used as ``filters'' when manufacturers report
drug and biologics shortages in order to limit the reporting of
potential supply chain disruptions that are not ``true drug shortage''
events. The comment stated that these factors might include market
dynamics and duration of supply chain shortage. With regard to market
dynamics, the comment stated that FDA should consider the number of
active suppliers and the percentage of the market supplied by such
active suppliers. The comment stated that using this as a filter would
help alert FDA to identify suppliers that are providing a significant
percent of the market and that truly have the potential to create a
drug shortage. For example, a market supplied by 10 active suppliers of
equal market share would not likely experience a drug shortage if 1 of
the active suppliers had a supply chain disruption. According to the
comment, the market void could be absorbed by the nine other active
suppliers via safety stock, additional production, etc. Therefore, the
comment recommended the addition of a ``primary suppliers'' filter to
separate those active suppliers who are supplying a significant percent
to the market (i.e., such as 20 percent or more of the market).
    In addition, the comment stated that the duration of a supply chain
shortage should be taken into consideration and utilized as a filter
regarding drug shortage reporting. This filter would consider the
typical inventory levels carried in the retail and wholesale channels.
For example, an active supplier may have a supply disruption (i.e.,
product out of stock) for 30 days; however, the market may not
experience

a drug shortage given the inventory levels in the retail and wholesale
channels. Typical inventory levels within these channels could range
from 30 to 60 days of supply; therefore, the comment proposed a 60-day
potential supply disruption as the minimum duration for drug shortage
reporting to avoid chances of inventory hoarding and artificial
increases in market demand that ultimately undermine the intent of
FDASIA.
    (Response) FDA declines to adopt the ``filters'' proposed to reduce
reporting under the rule. FDA does not agree that these proposed
``filters'' are consistent with the language or intent of FDASIA. As
explained in the preamble to the proposed rule (78 FR 65904 at 65912),
``meaningful disruption'' means a disruption in the applicant's own
supply. This interpretation avoids the problem of expecting an
applicant to predict the market-wide impact of its own interruption in
manufacturing, which can be difficult to assess and could lead to
inconsistent interpretation and less accurate predictions.
    (Comment 29) Two comments addressed the stockpile of VFC vaccines
maintained by CDC as part of its vaccine shortage notification program
and noted the success of the program in mitigating or completely
eliminating supply disruptions. One of the comments requested that FDA
permit applicants to take into consideration the existence of a CDC
stockpile in assessing whether an interruption in manufacturing is
reasonably likely to disrupt supply chains.
    (Response) We acknowledge the importance of the stockpile of VFC
vaccines maintained by CDC. CDC and HHS are required to maintain a
stockpile of routinely recommended vaccines for the United States in
the event of vaccine shortages or other unanticipated supply problems.
The national pediatric vaccines stockpile currently maintains 14
pediatric vaccines that protect infants, children, and adolescents from
15 vaccine-preventable diseases excluding influenza.\13\ Where
appropriate, FDA and the manufacturers work together with CDC and take
into consideration the existence of a CDC stockpile in assessing the
impact of supply disruptions and the likelihood of a shortage. However,
for the purposes of reporting under this rule, we do not agree that
applicants should be permitted to take into consideration the existence
of the CDC stockpile. As explained in section III.C.1.b.i, consistent
with the statutory definition of meaningful disruption, the rule
requires an applicant to report an interruption in manufacturing that
is likely to lead to a meaningful disruption in its own supply of a
covered drug or biological product. The rule does not require an
applicant to predict the market-wide impact of an interruption in its
own manufacturing, which can be difficult to accurately assess and
could lead to inconsistent interpretation of the regulation, less
accurate predictions, and under- or overreporting.
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    \13\ See http://www.cdc.gov/phpr/documents/VacStockpileManual.pdf.
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2. Timing and Submission of Notification
    (Comment 30) Three comments requested clarification of when the
notification ``clock'' would start, in other words, exactly when the
notification requirement would be triggered. Two of the comments
explained that at the outset, a meaningful disruption might not appear
``likely'' but may become ``likely'' as the events progress. The
comments expressed concern that the Agency and the applicant may
disagree about which event would trigger the notification requirement
if it was not obvious to the applicant initially that a meaningful
disruption would be likely. The comments suggested that the appropriate
trigger to start the notification ``clock'' is the date on which
information becomes available to the applicant from which it could be
reasonably determined that a meaningful disruption is likely to occur.
Another comment noted that the notification clock could begin on the
date of the event causing the interruption, or on the date the
applicant becomes aware that an interruption could cause a shortage.
The comment cautioned that if the latter were considered the trigger,
it may be difficult to determine the exact point in time.
    (Response) FDA expects that an applicant will notify FDA as soon as
information becomes available to the applicant from which the applicant
could reasonably determine that a meaningful disruption is likely to
occur. As explained in section III.C.2.a of this document and the
preamble to the proposed rule (78 FR 65904 at 65914), the applicant
should not wait until the interruption in manufacturing actually begins
to disrupt supply and affect patient access to the product. Early
notification is the Agency's best tool for addressing shortages because
it provides FDA with lead time to work with stakeholders to prevent the
shortage or mitigate the impact of an unavoidable shortage.
Accordingly, while not required, we encourage applicants to communicate
with FDA even in situations where a meaningful disruption may appear to
be possible though not necessarily likely.
    We understand the commenters' concern that FDA and the applicant
may disagree about which event would trigger the notification
requirement. FDA has sent and intends to continue sending noncompliance
letters when the Agency believes an applicant failed to notify FDA as
soon as practicable or within 5 business days of the discontinuance or
interruption.\14\ If an applicant receives a noncompliance letter but
believes the failure to notify was reasonable, the applicant should
provide a full explanation of the circumstances in the applicant's
response to the noncompliance letter. Consistent with section
506C(f)(3) of the FD&C Act, FDA will carefully consider the explanation
provided in determining whether there was a reasonable basis for not
notifying the Agency. If FDA determines that there was a reasonable
basis for not notifying the Agency in accordance with section 506C of
the FD&C Act and this rule, we will not post the noncompliance letter
or the applicant's response to FDA's Web site.
---------------------------------------------------------------------------

    \14\ As noted in section III.C.2.a, even if an applicant
notifies FDA within 5 business days of the discontinuance or
interruption, the applicant may be issued a noncompliance letter if
FDA believes the applicant did not notify the Agency as soon as
practicable.
---------------------------------------------------------------------------

    (Comment 31) Several comments addressed the proposal that if 6
months' advance notice is not possible, notification must be submitted
as soon as practicable thereafter, but in no case later than 5 business
days after the permanent discontinuance or interruption in
manufacturing occurs. Some comments expressed concern that FDA would
allow an applicant to report as late as 5 days after a permanent
discontinuance or interruption in manufacturing occurs. One comment
stated that this would significantly weaken the rule and limit its
effectiveness. The comment further stated that for an unforeseen
disruption or discontinuation, FDA should require immediate
notification or should outline what situations could arise that would
appropriately necessitate a 5-day reporting delay. One comment
expressed the view that reporting 5 days after the interruption should
only be considered acceptable in rare circumstances, such as natural
disaster. Another comment stated that applicants should be required to
notify FDA a minimum of 6 months prior to the discontinuance or
interruption, the only

exception being a natural disaster or catastrophic incident. The
comment stated that the proposed language is vague and lenient and
creates a loophole in mandatory reporting that ultimately serves
neither the public health nor that of patients, while shielding
manufacturers from their own failure to plan adequately.
    In contrast, some comments expressed concern that requiring
notification no later than 5 business days after the discontinuance or
interruption would not provide sufficient time for applicants to
investigate and get a complete understanding of the issue. The comments
explained that more than 5 business days may be necessary to confirm
whether actions taken in response to the interruption will affect the
manufacturer's ability to fill orders or meet expected demand. One
comment stated that requiring notification before a full investigation
has been completed is likely to lead to overreporting and less reliable
information being provided to FDA. The comment stated that the ``as
soon as practicable'' standard set forth in FDASIA provides the
necessary flexibility and should not be altered by adding a 5 business
day limit. One comment recommended that, if FDA believes a definite
reporting timeframe is necessary, it should be no shorter than 15 days
after the permanent discontinuance or interruption in manufacturing.
Another comment proposed that if a timeframe is necessary, it could be
extended to 15 days along with qualifying language, such as ``once it
can conclusively be determined that a manufacturing issue will
adversely impact supply.''
    (Response) FDA's most powerful tool for addressing drug and
biological product shortages is early notification, which provides lead
time for the Agency to work with manufacturers and other stakeholders
to prevent a shortage or to mitigate the impact of unavoidable
shortages. Accordingly, we expect that applicants will provide 6
months' advance notice whenever possible. FDA understands, though, 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. In those situations, FDA
requires notification ``as soon as practicable,'' but in no case more
than 5 business days after the interruption in manufacturing occurs.
The Agency has determined that 5 business days is adequate time for an
applicant to assess whether the discontinuance or interruption in
manufacturing is likely to lead to a meaningful disruption. As the
situation evolves, FDA expects that applicants will provide the Agency
with appropriate updates that will facilitate FDA's efforts. We believe
that this timeframe appropriately balances the need for early
notification and the understanding that applicants may not be able to
immediately assess the impact of an interruption in manufacturing.
    If notification was required only when an applicant has confirmed
that a meaningful disruption will occur, then it might be appropriate
to provide additional time for applicants to make this determination.
However, the statute requires notification when a discontinuance or
interruption in manufacturing is likely to lead to a meaningful
disruption. The statute takes account of the fact that there may be a
degree of uncertainty about the outcome of the discontinuance or
interruption. As such, we note that the qualifying language proposed by
one comment (i.e., adding ``once it can conclusively be determined that
a manufacturing issue will adversely impact supply'' to the
notification requirement) would not be consistent with the statutory
requirement to notify FDA when a discontinuance or interruption is
likely to lead to a meaningful disruption. FDA believes it is
reasonable for an applicant to make a determination about whether an
interruption is likely to lead to a meaningful disruption in supply
within 5 business days of the discontinuance or interruption. The
Agency does not believe that 15 business days should be necessary to
make such a determination, and a delay of 15 business days in
notification could have a significant impact on FDA's ability to
prevent or mitigate a shortage.
    We note that if an applicant receives a noncompliance letter for
failure to notify the Agency within 5 business days of a discontinuance
or interruption in manufacturing and believes that it would not have
been reasonable to expect the applicant to determine that the event was
likely to lead to a meaningful disruption, such information should be
provided in the applicant's response to the noncompliance letter. The
Agency, in turn, will consider that information in determining whether
the applicant had a reasonable basis for not notifying FDA within the