[Federal Register Volume 81, Number 207 (Wednesday, October 26, 2016)]
[Proposed Rules]
[Pages 74364-74368]
[FR Doc No: 2016-25850]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 2

[Docket No. FDA-2015-N-1355]
RIN 0910-AH36

Use of Ozone-Depleting Substances

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is
proposing to amend its regulation on uses of ozone-depleting substances
(ODSs), including chlorofluorocarbons (CFCs), to remove the designation
for certain products as ``essential uses'' under the Clean Air Act.
Essential-use products are exempt from the ban by

FDA on the use of CFCs and other ODS propellants in FDA-regulated
products and from the ban by the Environmental Protection Agency (EPA)
on the use of ODSs in pressurized dispensers. This action, if
finalized, will remove the essential-use exemptions for sterile aerosol
talc administered intrapleurally by thoracoscopy for human use and for
metered-dose atropine sulfate aerosol human drugs administered by oral
inhalation. FDA is proposing this action because alternative products
that do not use ODSs are now available and because these products are
no longer being marketed in versions that contain ODSs.

DATES: Submit either electronic or written comments on the proposed
rule by December 27, 2016. If FDA receives any significant adverse
comments, the Agency will publish a document withdrawing the direct
final rule before its effective date. FDA will then proceed to respond
to comments under this proposed rule using the usual notice-and-comment
procedures.

ADDRESSES: You may submit comments as follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to http://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on http://www.regulations.gov.
     If you want to submit a comment with confidential
information that you do not wish to be made available to the public
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper
submissions): Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Division of
Dockets Management, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No.
FDA-2015-N-1355 for ``Use of Ozone-Depleting Substances.'' Received
comments will be placed in the docket and, except for those submitted
as ``Confidential Submissions,'' publicly viewable at http://www.regulations.gov or at the Division of Dockets Management between 9
a.m. and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on http://www.regulations.gov.
Submit both copies to the Division of Dockets Management. If you do not
wish your name and contact information to be made publicly available,
you can provide this information on the cover sheet and not in the body
of your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: http://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to http://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Division of Dockets Management, 5630 Fishers
Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Daniel Orr, Center for Drug Evaluation
and Research, Food and Drug Administration, 10903 New Hampshire Ave.,
Bldg. 51, Rm. 6246, Silver Spring, MD 20993,<PHONE_NUMBER>,
<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION:

I. Background

    Production of ODSs has been phased out worldwide under the terms of
the Montreal Protocol on Substances that Deplete the Ozone Layer
(Montreal Protocol) (September 16, 1987, S. Treaty Doc. No. 10, 100th
Cong., 1st sess., 26 I.L.M. 1541 (1987)). In accordance with the
provisions of the Montreal Protocol, under authority of Title VI of the
Clean Air Act (section 601 et seq.), the manufacture of ODSs, including
CFCs, in the United States was generally banned as of January 1, 1996.
To receive permission to manufacture CFCs in the United States after
the phase-out date, manufacturers must obtain an exemption from the
phase-out requirements from the parties to the Montreal Protocol.
Procedures for securing an essential-use exemption under the Montreal
Protocol are described in a request by EPA for applications for
exemptions (60 FR 54349, October 23, 1995).
    A drug, device, cosmetic, or food contained in an aerosol product
or other pressurized dispenser that releases a CFC or other ODS
propellant is generally not considered an essential use of the ODS
under the Clean Air Act except as provided in Sec.  2.125(c) and (e)
(21 CFR 2.125(c) and (e)). This prohibition is based on scientific
research indicating that CFCs and other ODSs reduce the amount of ozone
in the stratosphere and thereby increase the amount of ultraviolet
radiation reaching the Earth. An increase in ultraviolet radiation will
increase the incidence of skin cancer, and produce other adverse
effects of unknown magnitude on humans, animals, and plants (80 FR
36937, June 29, 2015). Section 2.125(c) and (e) provide exemptions for
essential uses of ODSs for certain products containing ODS propellants
that FDA determines provide unique health benefits that would not be
available without the use of an ODS.
    Firms that wish to use ODSs manufactured after the phase-out date
in medical devices (as defined in section 601(8) of the Clean Air Act
(42 U.S.C. 7671(8)) covered under section 610 of the Clean Air Act (42
U.S.C. 7671i) must receive exemptions for essential uses under the
Montreal Protocol. EPA regulations implementing the provisions

of section 610 of the Clean Air Act contain a general ban on the use of
ODSs in pressurized dispensers, such as metered-dose inhalers (MDIs)
(40 CFR 82.64(c) and 82.66(d)). These EPA regulations exempt from the
general ban ``medical devices'' that FDA considers essential and that
are listed in Sec.  2.125(e). Section 601(8) of the Clean Air Act
defines ``medical device'' as any device (as defined in the Federal
Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 321), diagnostic
product, drug (as defined in the FD&C Act), and drug delivery system,
if such device, diagnostic product, drug, or drug delivery system uses
a class I or class II ODS for which no safe and effective alternative
has been developed (and, where necessary, has been approved by the
Commissioner of Food and Drugs), and if such device, diagnostic
product, drug, or drug delivery system has, after notice and
opportunity for public comment, been approved and determined to be
essential by the Commissioner in consultation with the Administrator of
EPA. Class I substances include CFCs, halons, carbon tetrachloride,
methyl chloroform, methyl bromide, and other chemicals not relevant to
this document (see 40 CFR part 82, appendix A to subpart A). Class II
substances include hydrochlorofluorocarbons (see 40 CFR part 82,
appendix B to subpart A).
    Faced with the statutorily mandated phase-out of the production of
ODSs, drug manufacturers have developed alternatives to MDIs and other
self-pressurized drug dosage forms that do not contain ODSs. Examples
of these alternative dosage forms are MDIs that use non-ODSs as
propellants and dry-powder inhalers. The availability of alternatives
to the ODSs means that certain drug products listed in Sec.  2.125(e)
are no longer essential uses of ODSs. Therefore, due to the lack of
marketing of approved products containing ODSs, and the availability of
alternative products that do not contain ODSs, FDA is proposing to
amend its regulations to remove essential-use designations for sterile
aerosol talc administered intrapleurally by thoracoscopy for human use
(Sec.  2.125(e)(4)(ix)) and for metered-dose atropine sulfate aerosol
human drugs administered by oral inhalation (Sec.  2.125(e)(4)(vi)).
    There is currently one sterile aerosol talc product containing ODSs
that is approved for administration intrapleurally by thoracoscopy for
human use for the treatment of recurrent malignant pleural effusion in
symptomatic patients. Section 2.125(g) sets forth standards for
determining whether the use of an ODS in a medical product is no longer
essential. Under Sec.  2.125(g)(3), an essential-use designation for
individual active moieties marketed as ODS products and represented by
one new drug application may no longer be essential if:
     At least one non-ODS product with the same active moiety
is marketed with the same route of administration, for the same
indication, and with approximately the same level of convenience of use
as the ODS product containing that active moiety;
     Supplies and production capacity for the non-ODS
product(s) exist or will exist at levels sufficient to meet patient
need;
     Adequate U.S. postmarketing-use data are available for the
non-ODS product(s); and
     Patients who medically require the ODS product are
adequately served by the non-ODS product(s) containing that active
moiety and other available products (Sec.  2.125(g)(3)).
    On June 29, 2015, FDA published a notice and request for comment
concerning its tentative conclusion that sterile aerosol talc
administered intrapleurally by thoracoscopy for human use no longer
constitutes an essential use under the Clean Air Act under the criteria
in (Sec.  2.125(g)(3). FDA requested comment on its findings that
sterile aerosol talc is currently marketed for intrapleural
administration in two non-ODS formulations and on its finding that the
route of administration, indications, and level of convenience appear
to be the same for the ODS and non-ODS formulations of sterile aerosol
talc. FDA also requested comment on its finding that the non-ODS
products are available in sufficient quantities to serve the current
patient population. FDA received no comments on these findings or on
its tentative conclusion that sterile aerosol talc administered
intrapleurally by thoracoscopy for human use no longer constitutes an
essential use of ODSs under the Clean Air Act.
    In the same document published on June 29, 2015, FDA requested
comments concerning its tentative conclusion that metered-dose atropine
sulfate aerosol human drugs administered by oral inhalation no longer
constitute an essential use under the Clean Air Act under the criteria
in (Sec.  2.125(g)(1). FDA requested comment concerning its finding
that metered-dose atropine sulfate aerosol human drugs administered by
oral inhalation are no longer marketed in an approved ODS formulation.
Under Sec.  2.125(g)(1), an active moiety may no longer constitute an
essential use (Sec.  2.125(e)) if it is no longer marketed in an
approved ODS formulation. The failure to market indicates
nonessentiality because the absence of a demand sufficient for even one
company to market the product is highly indicative that the use is not
essential. FDA received no comments concerning its finding that
metered-dose atropine sulfate aerosol human drugs administered by oral
inhalation are no longer marketed in an ODS formulation or concerning
its tentative conclusion that these drugs no longer constitute an
essential use of ODSs under the Clean Air Act.
    Accordingly, FDA is proposing to amend its regulation to remove
sterile aerosol talc administered intrapleurally by thoracoscopy for
human use (Sec.  2.125(e)(4)(ix)) and to remove metered-dose atropine
sulfate aerosol human drugs administered by oral inhalation (Sec.
2.125(e)(4)(vi)) as essential uses under the Clean Air Act.

II. Companion Rule to Direct Final Rulemaking

    This proposed rule is a companion document to the direct final rule
published elsewhere in this issue of the Federal Register. FDA is
proposing to amend Sec.  2.125 to remove essential-use designations for
sterile aerosol talc administered intrapleurally by thoracoscopy for
human use and for metered-dose atropine sulfate aerosol human drugs
administered by oral inhalation. This proposed rule is intended to make
noncontroversial changes to existing regulations. The Agency does not
anticipate receiving any significant adverse comment on this rule.
    Consistent with FDA's procedures on direct final rulemaking, we are
publishing elsewhere in this issue of the Federal Register a companion
direct final rule. The direct final rule and this companion proposed
rule are substantively identical. This companion proposed rule provides
the procedural framework within which the proposed rule may be
finalized in the event the direct final rule is withdrawn because of
any significant adverse comment. The comment period for this proposed
rule runs concurrently with the comment period of the companion direct
final rule. Any comments received in response to the companion direct
final rule will also be considered as comments regarding this proposed
rule.
    FDA is providing a comment period for the proposed rule of 60 days
after the date of publication in the Federal Register. If we receive a
significant adverse comment, we intend to withdraw the direct final
rule before its effective date by publishing a notice in the Federal
Register within 30 days

after the comment period ends. A significant adverse comment explains
why the rule either would be inappropriate, including challenges to the
rule's underlying premise or approach, or would be ineffective or
unacceptable without a change. In determining whether an adverse
comment is significant and warrants withdrawing a direct final rule,
the Agency will consider whether the comment raises an issue serious
enough to warrant a substantive response in a notice-and-comment
process in accordance with section 553 of the Administrative Procedure
Act (5 U.S.C. 553).
    Comments that are frivolous, insubstantial, or outside the scope of
the proposed rule will not be considered significant or adverse under
this procedure. For example, a comment recommending a regulation change
in addition to the changes in the proposed rule would not be considered
a significant adverse comment unless the comment states why the
proposed rule would be ineffective without the additional change. In
addition, if a significant adverse comment applies to an amendment,
paragraph, or section of this proposed rule and that provision can be
severed from the remainder of the rule, FDA may adopt as final the
provisions of the proposed rule that are not the subject of a
significant adverse comment.
    If FDA does not receive any significant adverse comment in response
to the proposed rule, the Agency will publish a document in the Federal
Register confirming the effective date of the direct final rule. The
Agency intends to make the direct final rule effective 30 days after
publication of the confirmation document in the Federal Register.
    A full description of FDA's policy on direct final rule procedures
may be found in a guidance for FDA and industry entitled ``Direct Final
Rule Procedures'' (available at http://www.fda.gov/RegulatoryInformation/Guidances/ucm125166.htm) that was announced in
the Federal Register on November 21, 1997 (62 FR 62466).

III. Economic Analysis of Impacts

A. Introduction

    We have examined the impacts of the proposed rule under Executive
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L.
104-4). Executive Orders 12866 and 13563 direct us to assess all costs
and benefits of available regulatory alternatives and, when regulation
is necessary, to select regulatory approaches that maximize net
benefits (including potential economic, environmental, public health
and safety, and other advantages; distributive impacts; and equity). We
have developed a comprehensive Economic Analysis of Impacts that
assesses the impacts of the proposed rule. We believe that this
proposed rule is not a significant regulatory action as defined by
Executive Order 12866.
    The Regulatory Flexibility Act requires us to analyze regulatory
options that would minimize any significant impact of a rule on small
entities. We propose to certify that the proposed rule will not have a
significant economic impact on a substantial number of small entities.
    The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires
us to prepare a written statement, which includes an assessment of
anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $146 million, using the most current (2015) Implicit
Price Deflator for the Gross Domestic Product. This proposed rule would
not result in an expenditure in any year that meets or exceeds this
amount.

B. Need for the Regulation

    This rule is necessary to comply with the Montreal Protocol under
authority of Title VI of the Clean Air Act (section 601 et seq.), which
banned the manufacture of ODSs, including CFCs, to reduce the depletion
of the ozone layer in the United States as of January 1, 1996. EPA
regulations exempted from the ban medical devices, diagnostic products,
drugs, and drug delivery systems that FDA considered essential and that
are listed in Sec.  2.125(e) when they use a class I or class II ODS
for which no safe and effective alternative has been developed. The
proposed rule would remove the exemptions for sterile aerosol talc
products and for metered-dose atropine sulfate aerosol human drugs
containing ODSs.
    There is currently at least one sterile aerosol talc product not
containing ODSs approved for administration intrapleurally by
thoracoscopy for human use that is a safe and effective alternative,
and which meets the criteria outlined in Sec.  2.125(g)(3).
Accordingly, the sterile aerosol talc product containing ODSs no longer
meets the requirements for essential use and should no longer be
exempted from the ban.
    Metered-dose atropine sulfate aerosol human drugs administered by
oral inhalation are no longer available in the product market in an
approved ODS formulation. The current absence of the product in the
market indicates both a lack of demand for the product and that the
product is nonessential, under Sec.  2.125(g)(1). With the adoption of
this rule, the manufacturer of the sterile aerosol talc with ODSs and
any potential future manufacturers of metered-dose atropine sulfate
aerosols will have notice of the requirement to comply with the ban of
products from containing ODSs.

C. Costs and Benefits

1. Number of Affected Entities
    The affected entities covered by this rule are the manufacturing
facilities of the products that would have exemptions from the ban
removed. Only one manufacturer, the Bryan Corporation that manufactures
the sterile aerosol talc product containing ODSs at a single facility,
would be affected. Currently, there are no manufacturers of metered-
dose atropine sulfate aerosols.
2. Costs
    The potential social costs from removing the exemptions are (1) the
costs to patient consumers or to their insurers for paying a higher
price for alternative non-ODS formulations of sterile aerosol talc
products and (2) the costs for disposing of and destroying any
remaining product inventory that remains after the effective date of
the final rule. We lack data about the stocks of product inventory that
are likely to remain after the effective date of the final rule and the
relative price that consumers or their insurers would pay. Because
significant notice has been given to the manufacturer about the
impending removal of the exemptions, we do not believe a significant
stock of inventory will remain for the sterile aerosol talc product.
The most recent publicly available information shows that the annual
revenues for Bryan Corporation are about $10 million (Ref. 1). Public
information about this company shows that it manufactures three
different surgical and medical instruments including the talc. If total
profits for the exempt talc product are 10 percent of the total annual
revenues, and if total revenues are exclusively from the exempt talc,
then $1 million represents an upper bound for the total social cost of
removing the sterile aerosol talc product from the market.

Because it is unlikely that the company's total profits are exclusively
from the sterile aerosol talc, it is more likely that the foregone
profits are at most one-third of the $1 million; in fact, the true
social cost could be significantly less than the total foregone profit
of this product.
    Metered-dose atropine sulfate aerosol human drugs that would be
affected by this rule are no longer marketed; consequently, removal of
the exemption for these products would not present the public,
consumers, insurers, or producers with any costs.
3. Health Benefits
    The proposed rule would implement the requirements of the Clean Air
Act that ban the use of products containing ODSs that no longer meet
the requirements for essential use. The social benefits of the proposed
rule derive from greater compliance with the Clean Air Act. The ODSs
that either would have been emitted by sterile aerosol talcs that
contain them, or from potential market entrants that would have
manufactured metered-dose atropine sulfate aerosols that contain ODSs
will no longer be emitting them, which will help reduce the depletion
of the ozone layer and the ultraviolet radiation reaching the Earth. We
lack the ability to quantify the health benefits from the reduced
exposure to and from the reduced risk associated with ultraviolet light
that result from removing the exemptions to the ban. Because the change
in exposure and resulting risk from the proposed rule is likely to be
small, the incremental health impact is likely to be too small to
measure.

D. Economic Summary

    The proposed rule, if finalized, will remove the exemptions for
sterile aerosol talc products and for metered-dose atropine sulfate
aerosol human drugs containing ODSs. The primary public health benefit
from adoption of the proposed rule is to reduce the depletion of the
ozone layer to decrease human exposure to ultraviolet radiation. The
reduction in exposure to ultraviolet radiation because of the rule is
likely to be too small to measure. The potential social costs of the
proposed rule would occur if patient consumers or their health care
insurers would have to pay more for otherwise comparable products and
if the product manufacturers would have to safely destroy any remaining
product inventories after the effective date of the rule. We estimate
that the social cost of the proposed rule is likely to be significantly
less than $1 million but no more than the upper-bound estimate of the
foregone annual profit of the company that manufactures the sterile
aerosol talc or $1 million. Because the metered-dose atropine sulfate
aerosol is not currently in the market, there would be no social cost
for removing its exemption from the ban.
    Imposing no new federal requirement is the baseline for a
regulatory analysis. With no new regulation, there are no compliance
costs or benefits to the proposed rule. However, because sterile
aerosol talc is no longer an essential use of ODSs, under the Clean Air
Act, there is no longer a pathway for sterile aerosol talc products
containing ODSs to remain on the market.

IV. Regulatory Flexibility Analysis

    FDA has examined the economic implications of the proposed rule as
required by the Regulatory Flexibility Act. If a rule will have a
significant economic impact on a substantial number of small entities,
the Regulatory Flexibility Act requires Agencies to analyze regulatory
options that would lessen the economic effect of the rule on small
entities. We certify that the final rule will not have a significant
economic impact on a substantial number of small entities. This
analysis, together with other relevant sections of this document,
serves as the proposed regulatory flexibility analysis, as required
under the Regulatory Flexibility Act.

V. Analysis of Environmental Impact

    We have determined under 21 CFR 25.30(h) that this action is of a
type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.

VI. Paperwork Reduction Act of 1995

    FDA tentatively concludes that this proposed rule contains no
collection of information. Therefore, clearance by the Office of
Management and Budget under the Paperwork Reduction Act of 1995 is not
required.

VII. Federalism

    We have analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. We have determined that
this proposed rule does not contain policies that have substantial
direct effects on the States, on the relationship between the National
Government and the States, or on the distribution of power and
responsibilities among the various levels of government. Accordingly,
we conclude that the rule does not contain policies that have
federalism implications as defined in the Executive order and,
consequently, a federalism summary impact statement is not required.

VIII. References

    The following reference is on display in the Division of Dockets
Management (see ADDRESSES) and is available for viewing by interested
persons between 9 a.m. and 4 p.m., Monday through Friday; it is also
available electronically at http://www.regulations.gov. FDA has
verified the Web site address, as of the date this document publishes
in the Federal Register, but Web sites are subject to change over time.

1. Bryan Corporation (http://listings.findthecompany.com/l/12165972/Bryan-Corporation-in-Woburn-MA, accessed on February 24, 2016).

List of Subjects in 21 CFR Part 2

    Administrative practice and procedure, Cosmetics, Drugs, Foods.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, we propose
that 21 CFR part 2 be amended as follows:

PART 2--GENERAL ADMINISTRATIVE RULINGS AND DECISIONS

0
1. The authority citation for part 2 continues to read as follows:

    Authority: 15 U.S.C. 402, 409; 21 U.S.C. 321, 331, 335, 342,
343, 346a, 348, 351, 352, 355, 360b, 361, 362, 371, 372, 374; 42
U.S.C. 7671 et seq.

Sec.  2.125   [Amended]

0
2. In Sec.  2.125, remove and reserve paragraphs (e)(4)(vi) and (ix).

    Dated: October 20, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-25850 Filed 10-25-16; 8:45 am]
 BILLING CODE 4164-01-P