List of Drug Products That Have Been Withdrawn or Removed From the Market for Reasons of Safety or Effectiveness, 63569-63574 [2018-26712]
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Federal Register / Vol. 83, No. 237 / Tuesday, December 11, 2018 / Rules and Regulations
certified that this rule, when
promulgated, does not have a significant
economic impact on a substantial
number of small entities under the
criteria of the Regulatory Flexibility Act.
Environmental Review
The FAA has determined that this
action, of modifying the descriptions of
VOR Federal airways V–318 and V–352
to reflect the removal of certain route
segments within Canadian airspace
deleted by NAV CANADA, qualifies for
categorical exclusion under the National
Environmental Policy Act and its
implementing regulations at 40 CFR part
1500, and in accordance with FAA
Order 1050.1F—Environmental Impacts:
Policies and Procedures, Paragraph 5–
6.5a, which categorically excludes from
further environmental impact review
rulemaking actions that designate or
modify classes of airspace areas,
airways, routes, and reporting points
(see 14 CFR part 71, Designation of
Class A, B, C, D, and E Airspace Areas;
Air Traffic Service Routes; and
Reporting Points). This action is not
expected to result in any potentially
significant environmental impacts. In
accordance with FAA Order 1050.1F,
paragraph 5–2 regarding Extraordinary
Circumstances, this action has been
reviewed for factors and circumstances
in which a normally categorically
excluded action may have a significant
environmental impact requiring further
analysis, and it is determined that no
extraordinary circumstances exist that
warrant preparation of an
environmental assessment.
Airspace, Incorporation by reference,
Navigation (air).
The Amendment
In consideration of the foregoing, the
Federal Aviation Administration
amends 14 CFR part 71 as follows:
PART 71—DESIGNATION OF CLASS A,
B, C, D, AND E AIRSPACE AREAS; AIR
TRAFFIC SERVICE ROUTES; AND
REPORTING POINTS
1. The authority citation for part 71
continues to read as follows:
■
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Authority: 49 U.S.C. 106(f), 106(g); 40103,
40113, 40120; E.O. 10854, 24 FR 9565, 3 CFR,
1959–1963 Comp., p. 389.
[Amended]
2. The incorporation by reference in
14 CFR 71.1 of FAA Order 7400.11C,
Airspace Designations and Reporting
Points, dated August 13, 2018 and
effective September 15, 2018, is
amended as follows:
■
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*
*
*
Domestic VOR Federal
*
*
V–318 [Amended]
From INT Beauce, PQ, Canada 103° and
Quebec, PQ, Canada, 047° radials; Houlton,
ME; INT Houlton 128° and St John, NB,
Canada, 267° radials; to St John. The airspace
within Canada is excluded.
V–352 [Amended]
From INT Beauce, PQ, Canada 085° and
Bangor, ME 336° radials; to Houlton, ME.
*
*
*
*
*
Issued in Washington, DC, on December 3,
2018.
Rodger A. Dean, Jr.,
Manager, Airspace Policy Group.
[FR Doc. 2018–26678 Filed 12–10–18; 8:45 am]
BILLING CODE 4910–13–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
21 CFR Part 216
[Docket No. FDA–2016–N–2462]
RIN 0910–AH35
List of Drug Products That Have Been
Withdrawn or Removed From the
Market for Reasons of Safety or
Effectiveness
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Final rule.
The Food and Drug
Administration (FDA, the Agency, or
we) is amending its regulations to revise
the list of drug products that have been
withdrawn or removed from the market
because such drug products or
components of such drug products have
been found to be unsafe or not effective.
Drug products appearing on this list
may not be compounded under the
exemptions provided by sections 503A
and 503B of the Federal Food, Drug, and
Cosmetic Act (FD&C Act). Specifically,
the final rule adds two entries to this list
of drug products.
DATES: This rule is effective January 10,
2019.
ADDRESSES: For access to the docket to
read background documents or
comments received, go to https://
www.regulations.gov and insert the
docket number found in brackets in the
heading of this final rule into the
‘‘Search’’ box and follow the prompts,
and/or go to the Dockets Management
Staff, 5630 Fishers Lane, Rm. 1061,
Rockville, MD 20852.
SUMMARY:
List of Subjects in 14 CFR Part 71
§ 71.1
Paragraph 6010(a)
Airways.
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63569
FOR FURTHER INFORMATION CONTACT:
Alexandria Fujisaki, Center for Drug
Evaluation and Research, Food and
Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 5169,
Silver Spring, MD 20993–0002, 301–
796–3110.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Executive Summary
A. Purpose of the Regulatory Action
B. Summary of the Major Provisions of the
Regulatory Action
C. Legal Authority
D. Costs and Benefits
II. Background
A. Relevant Provisions of the Statute
B. The List of Drug Products in § 216.24
C. Regulatory History of the List
III. Proposed Rule and Final Rule
A. Presentation to the Advisory Committee
B. The Proposed Rule
C. The Final Rule
IV. Comments on the Proposed Rule and
FDA’s Responses
A. Comments on Proposed Entries for
Inclusion on the List
B. Miscellaneous Comments
V. Legal Authority
VI. Analysis of Environmental Impact
VII. Economic Analysis of Impacts
VIII. Paperwork Reduction Act of 1995
IX. Consultation and Coordination With
Indian Tribal Governments
X. Federalism
XI. References
I. Executive Summary
A. Purpose of the Regulatory Action
FDA is amending its regulations to
revise the list of drug products that have
been withdrawn or removed from the
market because such drug products or
components of such drug products have
been found to be unsafe or not effective
(referred to as ‘‘the withdrawn or
removed list’’ or ‘‘the list’’) (§ 216.24 (21
CFR 216.24)). Drug products appearing
on the withdrawn or removed list may
not be compounded under the
exemptions provided by sections 503A
and 503B of the FD&C Act (21 U.S.C.
353a and 353b). In this final rule, the
Agency is finalizing in part the
proposed amendments to § 216.24 set
forth in the proposed rule published in
the Federal Register of October 18, 2016
(81 FR 71648).
B. Summary of the Major Provisions of
the Regulatory Action
After soliciting public comments and
consulting with the FDA Pharmacy
Compounding Advisory Committee (the
Committee), we are adding the
following entries to the list in § 216.24
of drug products that have been
withdrawn or removed from the market
because such drug products or
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components of such drug products have
been found to be unsafe or not effective:
Bromocriptine mesylate: All drug
products containing bromocriptine
mesylate for prevention of physiological
lactation.
Ondansetron hydrochloride: All
intravenous drug products containing
greater than a 16 milligram (mg) single
dose of ondansetron hydrochloride.
C. Legal Authority
Sections 503A, 503B, and 701(a) of
the FD&C Act (21 U.S.C. 353a, 353b, and
371(a)) provide the principal legal
authority for this final rule.
D. Costs and Benefits
The Agency is not aware of routine
compounding of the drug products that
are the subject of this final rule.
Therefore, we do not estimate any
compliance costs or loss of sales as a
result of the prohibition against
compounding these drug products for
human use. The Agency has determined
that this rulemaking is not a significant
regulatory action as defined by
Executive Order 12866.
II. Background
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A. Relevant Provisions of the Statute
Section 503A of the FD&C Act
describes the conditions that must be
satisfied for human drug products
compounded by a licensed pharmacist
or licensed physician to be exempt from
the following three sections of the FD&C
Act: (1) Section 501(a)(2)(B) (21 U.S.C.
351(a)(2)(B)) (concerning current good
manufacturing practice); (2) section
502(f)(1) (21 U.S.C. 352(f)(1))
(concerning the labeling of drugs with
adequate directions for use); and (3)
section 505 (21 U.S.C. 355) (concerning
the approval of new drugs under new
drug applications (NDAs) or abbreviated
new drug applications (ANDAs)).
In addition, section 503B of the FD&C
Act describes the conditions that must
be satisfied for a drug compounded for
human use by or under the direct
supervision of a licensed pharmacist in
an outsourcing facility to be exempt
from three sections of the FD&C Act: (1)
Section 502(f)(1), (2) section 505, and (3)
section 582 (21 U.S.C. 360eee–1)
(concerning drug supply chain security).
One of the conditions that must be
satisfied for a drug product to qualify for
the exemptions under sections 503A or
503B of the FD&C Act is that the
compounder does not compound a drug
product that appears on a list published
by the Secretary of Health and Human
Services (the Secretary) (delegated to
FDA) of drug products that have been
withdrawn or removed from the market
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because such drug products or
components of such drug products have
been found to be unsafe or not effective
(the withdrawn or removed list) (see
sections 503A(b)(1)(C), 503B(a)(4), and
503B(a)(11) of the FD&C Act).
B. The List of Drug Products in § 216.24
The drug products listed in the
withdrawn or removed list codified at
§ 216.24 have been withdrawn or
removed from the market because they
have been found to be unsafe or not
effective. A drug product that is
included in the withdrawn or removed
list is not eligible for the exemptions
provided in section 503A(a) from
sections 501(a)(2)(B), 502(f)(1), and 505
of the FD&C Act. In addition, a drug that
is included in the withdrawn or
removed list is not eligible for the
exemptions provided in section 503B(a)
from sections 502(f)(1), 505, and 582 of
the FD&C Act.
C. Regulatory History of the List
The Food and Drug Modernization
Act of 1997 (Pub. L. 105–115) added
section 503A to the FD&C Act. On
October 8, 1998, FDA proposed a rule in
the Federal Register (63 FR 54082) to
establish the original withdrawn or
removed list. On March 8, 1999, FDA
finalized this rule (64 FR 10944),
prohibiting the products described on
the original list from being compounded
under the exemptions provided by
section 503A(a) of the FD&C Act.
Following the addition of section
503B to the FD&C Act on November 27,
2013, through the enactment of the Drug
Quality and Security Act (Pub. L. 113–
54), FDA published a proposed rule to
revise and update the list in § 216.24 on
July 2, 2014 (79 FR 37687); FDA
published the final rule to amend
§ 216.24 in the Federal Register of
October 7, 2016 (81 FR 69668) (2016
final rule). Given that nearly identical
criteria apply for a drug to be included
on the list referred to in section
503A(b)(1)(C) and the list referred to in
section 503B(a)(4) of the FD&C Act, the
2016 final rule added language to
§ 216.24 clarifying that it applies for
purposes of both sections 503A and
503B.
III. Proposed Rule and Final Rule
A. Presentation to the Advisory
Committee
At a meeting held on June 17 and 18,
2015 (see the Federal Register of May
22, 2015 (80 FR 29717)), FDA presented
to the Committee FDA’s proposal to add
to the withdrawn or removed list all
drug products containing more than 325
mg of acetaminophen per dosage unit,
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all drug products containing aprotinin,
all drug products containing
bromocriptine mesylate for the
prevention of physiological lactation,
and all intravenous drug products
containing greater than a 16 mg single
dose of ondansetron hydrochloride. The
Committee voted in favor of including
each drug product entry on the list as
proposed by FDA.1
B. The Proposed Rule
In the Federal Register of October 18,
2016, FDA proposed to revise the
withdrawn or removed list to add all
drug products containing aprotinin, all
drug products containing bromocriptine
mesylate for the prevention of
physiological lactation, and all
intravenous drug products containing
greater than a 16 mg single dose of
ondansetron hydrochloride (October
2016 proposed rule). The addition of all
drug products containing more than 325
mg of acetaminophen per dosage unit to
the list was not included in the October
2016 proposed rule and remains under
consideration by the Agency.
C. The Final Rule
The Agency has considered the public
discussion and the advice provided by
the Committee regarding these matters
at the June 2015 meeting, as well as the
October 2016 proposed rule, including
the comments submitted on the
proposed rule (see section IV). Based on
the information before FDA and its own
knowledge and expertise, FDA is adding
two entries from the proposed rule to
the withdrawn or removed list in
§ 216.24.
The two entries FDA is adding to
§ 216.24 are as follows:
Bromocriptine mesylate: All drug
products containing bromocriptine
mesylate for prevention of physiological
lactation.
Ondansetron hydrochloride: All
intravenous drug products containing
greater than a 16 mg single dose of
ondansetron hydrochloride.
At this time, FDA is not finalizing the
entry in the proposed rule for all drug
products containing aprotinin. The
addition of an entry to the withdrawn or
removed list for drug products
containing aprotinin remains under
consideration by FDA.
1 A transcript of the June 2015 Committee
meeting (Ref. 1) and briefing information that
includes reviews and background on the proposed
entries (Ref. 2) may be found at the Dockets
Management Staff (see ADDRESSES) and at https://
wayback.archive-it.org/7993/20170111202622/
https://www.fda.gov/AdvisoryCommittees/
CommitteesMeetingMaterials/Drugs/Pharmacy
CompoundingAdvisoryCommittee/ucm431285.htm.
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IV. Comments on the Proposed Rule
and FDA’s Responses
Four comments, all from individuals,
were submitted on the October 2016
proposed rule. FDA has summarized
and responded to the relevant
comments in the following paragraphs.
A comment about ‘‘hernia repair with
mesh and plug’’ has not been answered
because it was not relevant to this
rulemaking. Comments regarding the
proposed addition of an entry to the
withdrawn or removed list for aprotinin
will not be answered at this time
because the entry remains under
consideration by FDA.
To make it easier to identify the
comments and FDA’s responses, the
word ‘‘Comment,’’ in parentheses,
appears before the comment’s
description, and the word ‘‘Response,’’
in parentheses, appears before the
Agency’s response. We have numbered
each comment to help distinguish
between different comments. Similar
comments are grouped together under
the same number, and, in some cases,
different subjects discussed in the same
comment are separated and designated
as distinct comments for purposes of
FDA’s response. The number assigned
to each comment or comment topic is
purely for organizational purposes and
does not signify the comment’s value or
importance or the order in which the
comments were received.
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A. Comments on Proposed Entries for
Inclusion on the List
1. Bromocriptine Mesylate
(Comment 1) One comment supported
the proposal to include all drug
products containing bromocriptine
mesylate for prevention of physiological
lactation on the withdrawn or removed
list.
(Response 1) FDA agrees with the
comment.
(Comment 2) FDA received one
comment opposing the proposal to
include all drug products containing
bromocriptine mesylate for prevention
of physiological lactation on the
withdrawn or removed list. The
comment asserts that bromocriptine
mesylate offers ‘‘significant
improvements in the quantity and
quality of life,’’ and, although it has
‘‘serious adverse effects,’’ the benefits of
bromocriptine mesylate compared to its
risks ‘‘should warrant continuous
approvability.’’
(Response 2) FDA disagrees with the
comment. For the reasons that follow,
FDA will add all drug products
containing bromocriptine mesylate for
prevention of physiological lactation to
the list in § 216.24.
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As a preliminary matter, the issue in
this rulemaking is whether all drug
products containing bromocriptine
mesylate for the indication of
prevention of physiological lactation
were withdrawn or removed from the
market because they were found to be
unsafe or not effective for this
indication. The criteria that must be met
to place a drug product on the
withdrawn or removed list are laid out
in the FD&C Act. Under sections 503A
and 503B of the FD&C Act, to be placed
on the withdrawn or removed list, drug
products must have been withdrawn or
removed from the market because such
drug products or components of such
drug products have been found to be
unsafe or not effective.
As FDA previously explained in the
October 2016 proposed rule, FDA
withdrew approval of PARLODEL
(bromocriptine mesylate, NDA 17962)
for the indication of prevention of
physiological lactation in a document
published in the Federal Register of
January 17, 1995 (60 FR 3404). At the
time, PARLODEL was the only marketed
drug product containing bromocriptine
mesylate labeled with this indication.
FDA’s 2015 ‘‘Review of Bromocriptine
Mesylate for the Withdrawn or Removed
List’’ indicates that the 1995 withdrawal
of PARLODEL for prevention of
physiological lactation was based on the
unfavorable benefit-risk balance of this
product for this indication. See ‘‘Review
of Bromocriptine Mesylate for the
Withdrawn or Removed List’’ in the
FDA Briefing Document for the June 17
and 18, 2015 Pharmacy Compounding
Advisory Committee Meeting, available
at https://wayback.archive-it.org/7993/
20170113060809/https://www.fda.gov/
AdvisoryCommittees/Committees
MeetingMaterials/Drugs/Pharmacy
CompoundingAdvisoryCommittee/
ucm449533.htm. In particular, in a
notice published in the Federal Register
on August 23, 1994 (59 FR 43347), FDA
concluded that bromocriptine
mesylate’s risks of hypertension,
seizures, and cardiovascular accidents
outweighed the product’s marginal
benefit in preventing postpartum
lactation, which can be suppressed
without risk by using more
conservative, nonpharmacological
treatments. Withdrawal of PARLODEL’s
indication for the prevention of
physiological lactation became effective
on February 16, 1995 (60 FR 3404). FDA
has determined that all drug products
containing bromocriptine mesylate for
prevention of physiological lactation
were withdrawn or removed from the
market because such products have
been found to be unsafe or not effective.
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We note that FDA-approved drug
products containing bromocriptine
mesylate for other indications, such as
treatment of Parkinson’s disease,
acromegaly, and prolactin-secreting
adenomas, remain marketed.
FDA’s 2015 review, which included a
discussion of the withdrawal of
PARLODEL’s indication for the
prevention of physiological lactation,
was presented to the Committee at the
meeting held on June 17 and 18, 2015,
and the Committee voted in favor of the
Agency’s proposal to include all drug
products containing bromocriptine
mesylate for the prevention of
physiological lactation on the list. For
these reasons, FDA proposed in the
October 2016 proposed rule to include
all drug products containing
bromocriptine mesylate for the
prevention of physiological lactation on
the withdrawn or removed list.
The comment offered no scientific
rationale or support for its position that
this drug product should not be on the
list; therefore, FDA is including
bromocriptine mesylate for prevention
of physiological lactation on the
withdrawn or removed list.
2. Ondansetron Hydrochloride
(Comment 3) One comment supported
the proposal to include all intravenous
drug products containing greater than a
16 mg single dose of ondansetron
hydrochloride on the withdrawn or
removed list.
(Response 3) FDA agrees with the
comment.
(Comment 4) FDA received one
comment on the proposal to include all
intravenous drug products containing
greater than a 16 mg single dose of
ondansetron hydrochloride suggesting
‘‘perhaps there is more to investigate
and stricter regulation of the
administration of IV ondansetron
hydrochloride is warranted in the
future.’’
(Response 4) FDA intends to monitor
future approvals, withdrawals, or
removals of drugs, to consider other
relevant information that may suggest
the need to revise the withdrawn or
removed list, and to propose
modifications as appropriate. In
addition, members of the public can
submit a citizen petition at any time
under 21 CFR 10.25 and 10.30
requesting that FDA add, modify, or
remove an entry on the list (with data
to support their request), and FDA will
consider and respond to the petition.
(Comment 5) FDA received one
comment opposing the proposal to
include all intravenous drug products
containing greater than a 16 mg single
dose of ondansetron hydrochloride on
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the withdrawn or removed list. The
comment asserts that ondansetron
hydrochloride offers ‘‘significant
improvements in the quantity and
quality of life,’’ and, although it has
‘‘serious adverse effects,’’ the benefits of
ondansetron hydrochloride compared to
its risks ‘‘should warrant continuous
approvability.’’
(Response 5) FDA disagrees with the
comment. For the reasons that follow,
FDA will add all intravenous drug
products containing greater than a 16
mg single dose of ondansetron
hydrochloride to the list in § 216.24.
As noted earlier, the issue in this
rulemaking is whether drug products
containing greater than a 16 mg single
dose of ondansetron hydrochloride were
withdrawn or removed from the market
because they were found to be unsafe or
not effective.
As FDA previously explained in the
October 2016 proposed rule, in the
Federal Register of June 10, 2015 (80 FR
32962), FDA announced its
determination under 21 CFR 314.161
and 314.162(a)(2) that the NDA for
Ondansetron (ondansetron
hydrochloride) Injection, USP, 32 mg/50
mL, single IV dose was withdrawn from
sale for reasons of safety. In particular,
this product was associated with a
specific type of irregular heart rhythm
called QT interval prolongation, and the
data suggest that any dose above the
maximum recommendation of 16 mg
per dose intravenously has the potential
for increased risk of QT prolongation.
FDA made this determination after
holders of one NDA and four ANDAs
voluntarily removed such products from
the market and requested that FDA
withdraw approval of their respective
applications under 21 CFR 314.150(d).
Thus, all drug products containing
greater than a 16 mg single dose of
ondansetron hydrochloride have been
withdrawn or removed from the market
because such drug products have been
found to be unsafe or not effective. We
note that FDA-approved drug products
containing lower single doses of
ondansetron hydrochloride remain
marketed.
FDA’s review of intravenous drug
products containing greater than a 16
mg single dose of ondansetron
hydrochloride was presented to the
Committee at the meeting held on June
17 and 18, 2015, and the Committee
voted in favor of the Agency’s proposal
to include all intravenous drug products
containing greater than a 16 mg single
dose of ondansetron hydrochloride on
the list. For these reasons, FDA
proposed in the October 2016 proposed
rule to include all intravenous drug
products containing greater than a 16
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mg single dose of ondansetron
hydrochloride on the withdrawn or
removed list.
(Comment 6) FDA received one
comment asserting that ondansetron
hydrochloride should not be
recommended for use by pregnant
women because it was not approved by
FDA for pregnant women.
(Response 6) This comment is outside
the scope of this rulemaking.
Compounded drugs are not FDA
approved and this rulemaking addresses
the placement of certain drug products
on the withdrawn or removed list,
including all intravenous drug products
containing greater than a 16 mg single
dose of ondansetron hydrochloride. As
previously noted, drugs appearing on
this list may not be compounded under
the exemptions provided by sections
503A and 503B of the FD&C Act.
Therefore, to the extent the commenter
believes that intravenous drug products
containing greater than a 16 mg single
dose of ondansetron hydrochloride
should not be compounded for pregnant
women under the exemptions provided
by sections 503A and 503B of the FD&C
Act, we agree. The addition of the entry
FDA is finalizing regarding ondansetron
hydrochloride through this rulemaking
for the list in § 216.24 will prohibit
compounding of intravenous drug
products containing greater than a 16
mg single dose of ondansetron
hydrochloride under the exemptions
provided by sections 503A and 503B of
the FD&C Act for all patients, including
pregnant women.
V. Legal Authority
Sections 503A and 503B of the FD&C
Act provide the principal legal authority
for this final rule. As described
previously in section II, section 503A of
the FD&C Act describes the conditions
that must be satisfied for human drug
products compounded by a licensed
pharmacist or licensed physician to be
exempt from three sections of the FD&C
Act (sections 501(a)(2)(B), 502(f)(1), and
505). One of the conditions that must be
satisfied to qualify for the exemptions
under section 503A of the FD&C Act is
that the licensed pharmacist or licensed
physician does not compound a drug
product that appears on a list published
by FDA in the Federal Register of drug
products that have been withdrawn or
removed from the market because such
drug products or components of such
drug products have been found to be
unsafe or not effective (see section
503A(b)(1)(C) of the FD&C Act). Section
503A(c)(1) of the FD&C Act also states
that the Secretary shall issue regulations
to implement section 503A, and that
before issuing regulations to implement
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section 503A(b)(1)(C) pertaining to the
withdrawn or removed list, among other
sections, the Secretary shall convene
and consult an advisory committee on
compounding unless the Secretary
determines that the issuance of such
regulations before consultation is
necessary to protect the public health.2
Section 503B of the FD&C Act
describes the conditions that must be
satisfied for a drug compounded for
human use by or under the direct
supervision of a licensed pharmacist in
an outsourcing facility to be exempt
from three sections of the FD&C Act
(sections 502(f)(1), 505, and 582). One of
the conditions in section 503B of the
FD&C Act that must be satisfied to
qualify for the exemptions is that the
drug does not appear on a list published
by FDA of drugs that have been
withdrawn or removed from the market
because such drugs or components of
such drugs have been found to be unsafe
or not effective (see section 503B(a)(4)).
To be eligible for the exemptions in
section 503B, a drug must be
compounded in an outsourcing facility
in which the compounding of drugs
occurs only in accordance with section
503B, including as provided in section
503B(a)(4) of the FD&C Act.
Thus, sections 503A and 503B of the
FD&C Act, in conjunction with our
general rulemaking authority in section
701(a) of the FD&C Act (21 U.S.C.
371(a)), serve as our principal legal
authority for this final rule revising
FDA’s regulation on the list of drug
products withdrawn or removed from
the market because such drug products
or components of such drug products
have been found to be unsafe or not
effective in § 216.24.
VI. 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.
VII. Economic Analysis of Impacts
We have examined the impacts of the
final rule under Executive Order 12866,
Executive Order 13563, Executive Order
13771, 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
2 Note: The functions of the Secretary described
herein have been delegated to FDA.
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Federal Register / Vol. 83, No. 237 / Tuesday, December 11, 2018 / Rules and Regulations
necessary, to select regulatory
approaches that maximize net benefits
(including potential economic,
environmental, public health and safety,
and other advantages; distributive
impacts; and equity). Executive Order
13771 requires that the costs associated
with significant new regulations ‘‘shall,
to the extent permitted by law, be offset
by the elimination of existing costs
associated with at least two prior
regulations.’’ This final rule is not a
significant regulatory action as defined
by Executive Order 12866 and is not
subject to Executive Order 13771.
The Regulatory Flexibility Act
requires us to analyze regulatory options
that would minimize any significant
impact of a rule on small entities.
Because small businesses are not
expected to incur any compliance costs
or loss of sales due to this regulation, we
certify that the final 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 issuing ‘‘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 $150 million, using the
most current (2017) Implicit Price
Deflator for the Gross Domestic Product.
This final rule is not expected to result
in an expenditure in any year that
would meet or exceed this amount.
This final rule amends § 216.24
concerning human drug compounding.
Specifically, the final rule adds to the
list of drug products that may not be
compounded under the exemptions
provided by sections 503A and 503B of
the FD&C Act because the drug products
have been withdrawn or removed from
the market because such drug products
or components of such drug products
have been found to be unsafe or not
effective (see section II). We are adding
two entries to the list: Drug products
containing bromocriptine mesylate for
prevention of physiological lactation
and intravenous drug products
containing greater than a 16 mg single
dose of ondansetron hydrochloride. The
Agency is not aware of routine
compounding of these drug products;
therefore, we do not estimate any
compliance costs or loss of sales as a
result of the prohibition against
compounding these drugs for human
use.
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Unless we certify that a rule will not
have a significant economic impact on
a substantial number of small entities,
the Regulatory Flexibility Act requires
us to analyze regulatory options to
minimize any significant economic
impact of a regulation on small entities.
Most pharmacies meet the Small
Business Administration definition of a
small entity, which is defined as having
annual sales less than $27.5 million for
this industry. We are not aware of any
routine compounding of the drug
products that are the subject of this final
rule and do not estimate any
compliance costs or loss of sales to
small businesses as a result of the
prohibition against compounding these
drug products. Therefore, we certify that
this final rule will not have a significant
economic impact on a substantial
number of small entities.
VIII. Paperwork Reduction Act of 1995
This final rule contains no collections
of information. Therefore, clearance by
the Office of Management and Budget
under the Paperwork Reduction Act of
1995 is not required.
IX. Consultation and Coordination With
Indian Tribal Governments
We have analyzed this rule in
accordance with the principles set forth
in Executive Order 13175. We have
determined that the rule does not
contain policies that have substantial
direct effects on one or more Indian
Tribes, on the relationship between the
Federal Government and Indian Tribes,
or on the distribution of power and
responsibilities between the Federal
Government and Indian Tribes.
Accordingly, we conclude that the rule
does not contain policies that have
tribal implications as defined in the
Executive Order and, consequently, a
tribal summary impact statement is not
required.
X. Federalism
We have analyzed this final rule in
accordance with the principles set forth
in Executive Order 13132. FDA has
determined that the final rule does not
contain policies that have substantial
direct effects on the States, on the
relationship between the National
Government and the States, or on the
distribution of power and
responsibilities among the various
levels of government. Accordingly, the
Agency concludes 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.
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63573
XI. References
The following references are on
display in the Dockets Management
Staff (see ADDRESSES) and are available
for viewing by interested persons
between 9 a.m. and 4 p.m., Monday
through Friday; they are also available
electronically at https://
www.regulations.gov. FDA has verified
the website addresses, as of the date this
document publishes in the Federal
Register, but websites are subject to
change over time.
1. Transcript for the June 17–18, 2015,
Meeting of the Pharmacy Compounding
Advisory Committee, available at https://
wayback.archive-it.org/7993/2017011
1202622/https://www.fda.gov/
AdvisoryCommittees/CommitteesMee
tingMaterials/Drugs/Pharmacy
CompoundingAdvisoryCommittee/
ucm431285.htm.
2. Briefing Information for the June 17–18,
2015, Meeting of the Pharmacy
Compounding Advisory Committee, available
at https://wayback.archive-it.org/7993/
20170111202622/https://www.fda.gov/
AdvisoryCommittees/CommitteesMeeting
Materials/Drugs/PharmacyCompounding
AdvisoryCommittee/ucm431285.htm.
List of Subjects in 21 CFR Part 216
Drugs, Prescription drugs.
Therefore, under the Federal Food,
Drug, and Cosmetic Act and under
authority delegated to the Commissioner
of Food and Drugs, 21 CFR part 216 is
amended as follows:
PART 216—HUMAN DRUG
COMPOUNDING
1. The authority citation for part 216
continues to read as follows:
■
Authority: 21 U.S.C. 351, 352, 353a, 353b,
355, and 371.
2. Amend § 216.24 by adding, in
alphabetical order, to the list of drugs
‘‘Bromocriptine mesylate’’ and
‘‘Ondansetron hydrochloride’’ to read as
follows:
■
§ 216.24 Drug products withdrawn or
removed from the market for reasons of
safety or effectiveness.
*
*
*
*
*
Bromocriptine mesylate: All drug
products containing bromocriptine
mesylate for prevention of physiological
lactation.
*
*
*
*
*
Ondansetron hydrochloride: All
intravenous drug products containing
greater than a 16 milligram single dose
of ondansetron hydrochloride.
*
*
*
*
*
E:\FR\FM\11DER1.SGM
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Federal Register / Vol. 83, No. 237 / Tuesday, December 11, 2018 / Rules and Regulations
Dated: December 4, 2018.
Scott Gottlieb,
Commissioner of Food and Drugs.
[FR Doc. 2018–26712 Filed 12–10–18; 8:45 am]
BILLING CODE 4164–01–P
DEPARTMENT OF DEFENSE
Office of the Secretary
32 CFR Part 199
[DOD–2018–HA–0062]
RIN 0720–AB75
TRICARE Pharmacy Benefits Program
Reforms
Office of the Secretary,
Department of Defense (DoD).
ACTION: Interim final rule.
AGENCY:
This interim final rule
implements Section 702 of the National
Defense Authorization Act for Fiscal
Year 2018 (NDAA FY18). The law
makes significant changes to the
TRICARE Pharmacy Benefits Program,
specifically it: Updates co-payment
requirements; authorizes a new process
for encouraging use of pharmaceutical
agents that provide the best clinical
effectiveness by excluding coverage for
particular pharmaceutical agents that
provide very little or no clinical
effectiveness relative to similar agents
and for giving preferential status to
agents that provide enhanced clinical
effectiveness; and authorizes special
reimbursement methods, amounts, and
procedures to encourage use or highvalue products and discourage use of
low-value products with respect to
pharmaceutical agents provided as part
of medical services from authorized
providers.
SUMMARY:
This interim final rule is
effective December 11, 2018. Comments
must be received by February 11, 2019.
FOR FURTHER INFORMATION CONTACT:
David W. Bobb, RPh, JD, Chief,
Pharmacy Operations, Defense Health
Agency (DHA), telephone (703) 681–
2890.
DATES:
SUPPLEMENTARY INFORMATION:
I. Executive Summary
amozie on DSK3GDR082PROD with RULES
A. Purpose of the Interim Final Rule
This interim final rule implements
Section 702 of the National Defense
Authorization Act for Fiscal Year 2018
(NDAA FY18), which does three things:
(1) It updates cost-sharing requirements
for outpatient pharmaceutical
prescriptions filled by retail pharmacies
and the TRICARE mail order pharmacy
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program. (2) It authorizes a new
Uniform Formulary process for
encouraging use of pharmaceutical
agents in the TRICARE Pharmacy
Benefits Program that provide the best
clinical effectiveness by excluding
coverage for particular pharmaceutical
agents that provide very little or no
clinical effectiveness relative to similar
agents and giving preferential status to
agents that provide enhanced clinical
effectiveness. (3) It authorizes special
reimbursement methods, amounts, and
procedures to encourage use of highvalue products and discourage use of
low-value products with respect to
pharmaceutical agents provided as part
of medical services from authorized
providers. This interim final rule
implements each of these three statutory
changes. This is being issued as an
interim final rule in order to implement
expeditiously the reforms authorized by
Section 702, as specifically authorized
by subsection (b)(3) of that section.
Based on that clear Congressional
authority and intent, the Department
finds that obtaining public comment in
advance of issuing this rule is
impracticable, unnecessary, and
contrary to the public interest. Delaying
expeditious implementation by waiting
for public comments to this interim rule
not only delays the significant cost
savings to the government that will be
realized through implementation but
also continues to allow coverage of
pharmaceutical agents that do not
provide the best clinical effectiveness
for beneficiaries. In addition, subsection
(b)(3) of Section 702 states that ‘‘in order
to implement expeditiously the reforms
authorized . . . (A) the Secretary of
Defense may prescribe an interim final
rule, (B) not later than one year after
prescribing the interim final rule and
considering public comments with
respect to such interim final rule, by
prescribing a final rule.’’ Clearly
Congressional intent is to implement the
authorized reforms quickly.
Nonetheless, DoD invites public
comments on this rule and is committed
to considering all comments and issuing
a final rule as soon as practicable (but
not later than one year after issuance of
this interim final rule).
B. Legal Authority for the Regulatory
Action
This interim final rule is under the
primary authority of 10 U.S.C. 1074g,
1079 and 1086, and Section 702 of
NDAA–18. Specifically, section
702(b)(3) of NDAA–18 authorizes DoD
to ‘‘prescribe such changes to the
regulations implementing the TRICARE
program . . . by prescribing an interim
final rule.’’ TRICARE program
PO 00000
Frm 00016
Fmt 4700
Sfmt 4700
regulations (32 CFR part 199) are issued
under statutory authorities including 10
U.S.C. 1074g (the Pharmacy Benefits
Program) and 10 U.S.C. 1079 and 1086
(TRICARE medical benefits). Section
702 of NDAA–18 amends both section
1074g and section 1079 (the section
1079 amendment being automatically
applicable to section 1086).
C. Summary of Major Provisions of the
Interim Final Rule
The major provisions of the interim
final rule are the following.
1. Updating Cost-Sharing. Under the
authority of section 1074g(a)(6), as
amended by Section 702(a) of NDAA
FY18, we are amending 32 CFR
199.21(i) to cross reference the statutory
changes.
2. Uniform Formulary Changes. Based
on section 1074g(a)(10), as added by
Section 702(b)(1) of NDAA FY 18, we
are changing the Uniform Formulary
process under 32 CFR 199.21(e) by
authorizing the exclusion of any
pharmaceutical agent that provides very
little or no clinical effectiveness relative
to similar agents, and preferential status
for pharmaceutical agents that have
enhanced clinical effectiveness relative
to similar agents.
3. Pharmaceutical Agents as Part of
Medical Services. Based on 10 U.S.C.
1079(q), as added by Section 702(b)(2)
of NDAA FY18, we are changing
provisions of 32 CFR 199.14 to
authorize the adoption of special
reimbursement methods, amounts and
procedures to encourage the use of high
value products and discourage the use
of low value products—both relative to
similar agents—in connection with
pharmaceutical agents provided as part
of outpatient medical services covered
by TRICARE.
II. Provisions of Interim Final Rule
A. Updating Co-Payments
The interim final rule amends 32 CFR
199.21(i)(2), which is the paragraph of
the TRICARE regulation that governs
cost-sharing amounts under the
Pharmacy Benefits Program. The
amended language simply cross
references the statutory specifications
on cost-sharing, including the table set
forth in 10 U.S.C. 1074g(a)(6)(A). This
table lists cost sharing amounts for the
years 2018 through 2027 for generic,
formulary, and non-formulary
pharmaceutical agents dispensed by
retail network pharmacies and the mail
order pharmacy program. Two
exceptions are that there is a $0 costshare for vaccines/immunizations
authorized as preventive care for
eligible beneficiaries and provided by
E:\FR\FM\11DER1.SGM
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]]>Agencies
[Federal Register Volume 83, Number 237 (Tuesday, December 11, 2018)]
[Rules and Regulations]
[Pages 63569-63574]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-26712]
=======================================================================
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 216
[Docket No. FDA-2016-N-2462]
RIN 0910-AH35
List of Drug Products That Have Been Withdrawn or Removed From
the Market for Reasons of Safety or Effectiveness
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is
amending its regulations to revise the list of drug products that have
been withdrawn or removed from the market because such drug products or
components of such drug products have been found to be unsafe or not
effective. Drug products appearing on this list may not be compounded
under the exemptions provided by sections 503A and 503B of the Federal
Food, Drug, and Cosmetic Act (FD&C Act). Specifically, the final rule
adds two entries to this list of drug products.
DATES: This rule is effective January 10, 2019.
ADDRESSES: For access to the docket to read background documents or
comments received, go to https://www.regulations.gov and insert the
docket number found in brackets in the heading of this final rule into
the ``Search'' box and follow the prompts, and/or go to the Dockets
Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Alexandria Fujisaki, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 5169, Silver Spring, MD 20993-0002, 301-
796-3110.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Executive Summary
A. Purpose of the Regulatory Action
B. Summary of the Major Provisions of the Regulatory Action
C. Legal Authority
D. Costs and Benefits
II. Background
A. Relevant Provisions of the Statute
B. The List of Drug Products in Sec. 216.24
C. Regulatory History of the List
III. Proposed Rule and Final Rule
A. Presentation to the Advisory Committee
B. The Proposed Rule
C. The Final Rule
IV. Comments on the Proposed Rule and FDA's Responses
A. Comments on Proposed Entries for Inclusion on the List
B. Miscellaneous Comments
V. Legal Authority
VI. Analysis of Environmental Impact
VII. Economic Analysis of Impacts
VIII. Paperwork Reduction Act of 1995
IX. Consultation and Coordination With Indian Tribal Governments
X. Federalism
XI. References
I. Executive Summary
A. Purpose of the Regulatory Action
FDA is amending its regulations to revise the list of drug products
that have been withdrawn or removed from the market because such drug
products or components of such drug products have been found to be
unsafe or not effective (referred to as ``the withdrawn or removed
list'' or ``the list'') (Sec. 216.24 (21 CFR 216.24)). Drug products
appearing on the withdrawn or removed list may not be compounded under
the exemptions provided by sections 503A and 503B of the FD&C Act (21
U.S.C. 353a and 353b). In this final rule, the Agency is finalizing in
part the proposed amendments to Sec. 216.24 set forth in the proposed
rule published in the Federal Register of October 18, 2016 (81 FR
71648).
B. Summary of the Major Provisions of the Regulatory Action
After soliciting public comments and consulting with the FDA
Pharmacy Compounding Advisory Committee (the Committee), we are adding
the following entries to the list in Sec. 216.24 of drug products that
have been withdrawn or removed from the market because such drug
products or
[[Page 63570]]
components of such drug products have been found to be unsafe or not
effective:
Bromocriptine mesylate: All drug products containing bromocriptine
mesylate for prevention of physiological lactation.
Ondansetron hydrochloride: All intravenous drug products containing
greater than a 16 milligram (mg) single dose of ondansetron
hydrochloride.
C. Legal Authority
Sections 503A, 503B, and 701(a) of the FD&C Act (21 U.S.C. 353a,
353b, and 371(a)) provide the principal legal authority for this final
rule.
D. Costs and Benefits
The Agency is not aware of routine compounding of the drug products
that are the subject of this final rule. Therefore, we do not estimate
any compliance costs or loss of sales as a result of the prohibition
against compounding these drug products for human use. The Agency has
determined that this rulemaking is not a significant regulatory action
as defined by Executive Order 12866.
II. Background
A. Relevant Provisions of the Statute
Section 503A of the FD&C Act describes the conditions that must be
satisfied for human drug products compounded by a licensed pharmacist
or licensed physician to be exempt from the following three sections of
the FD&C Act: (1) Section 501(a)(2)(B) (21 U.S.C. 351(a)(2)(B))
(concerning current good manufacturing practice); (2) section 502(f)(1)
(21 U.S.C. 352(f)(1)) (concerning the labeling of drugs with adequate
directions for use); and (3) section 505 (21 U.S.C. 355) (concerning
the approval of new drugs under new drug applications (NDAs) or
abbreviated new drug applications (ANDAs)).
In addition, section 503B of the FD&C Act describes the conditions
that must be satisfied for a drug compounded for human use by or under
the direct supervision of a licensed pharmacist in an outsourcing
facility to be exempt from three sections of the FD&C Act: (1) Section
502(f)(1), (2) section 505, and (3) section 582 (21 U.S.C. 360eee-1)
(concerning drug supply chain security).
One of the conditions that must be satisfied for a drug product to
qualify for the exemptions under sections 503A or 503B of the FD&C Act
is that the compounder does not compound a drug product that appears on
a list published by the Secretary of Health and Human Services (the
Secretary) (delegated to FDA) of drug products that have been withdrawn
or removed from the market because such drug products or components of
such drug products have been found to be unsafe or not effective (the
withdrawn or removed list) (see sections 503A(b)(1)(C), 503B(a)(4), and
503B(a)(11) of the FD&C Act).
B. The List of Drug Products in Sec. 216.24
The drug products listed in the withdrawn or removed list codified
at Sec. 216.24 have been withdrawn or removed from the market because
they have been found to be unsafe or not effective. A drug product that
is included in the withdrawn or removed list is not eligible for the
exemptions provided in section 503A(a) from sections 501(a)(2)(B),
502(f)(1), and 505 of the FD&C Act. In addition, a drug that is
included in the withdrawn or removed list is not eligible for the
exemptions provided in section 503B(a) from sections 502(f)(1), 505,
and 582 of the FD&C Act.
C. Regulatory History of the List
The Food and Drug Modernization Act of 1997 (Pub. L. 105-115) added
section 503A to the FD&C Act. On October 8, 1998, FDA proposed a rule
in the Federal Register (63 FR 54082) to establish the original
withdrawn or removed list. On March 8, 1999, FDA finalized this rule
(64 FR 10944), prohibiting the products described on the original list
from being compounded under the exemptions provided by section 503A(a)
of the FD&C Act.
Following the addition of section 503B to the FD&C Act on November
27, 2013, through the enactment of the Drug Quality and Security Act
(Pub. L. 113-54), FDA published a proposed rule to revise and update
the list in Sec. 216.24 on July 2, 2014 (79 FR 37687); FDA published
the final rule to amend Sec. 216.24 in the Federal Register of October
7, 2016 (81 FR 69668) (2016 final rule). Given that nearly identical
criteria apply for a drug to be included on the list referred to in
section 503A(b)(1)(C) and the list referred to in section 503B(a)(4) of
the FD&C Act, the 2016 final rule added language to Sec. 216.24
clarifying that it applies for purposes of both sections 503A and 503B.
III. Proposed Rule and Final Rule
A. Presentation to the Advisory Committee
At a meeting held on June 17 and 18, 2015 (see the Federal Register
of May 22, 2015 (80 FR 29717)), FDA presented to the Committee FDA's
proposal to add to the withdrawn or removed list all drug products
containing more than 325 mg of acetaminophen per dosage unit, all drug
products containing aprotinin, all drug products containing
bromocriptine mesylate for the prevention of physiological lactation,
and all intravenous drug products containing greater than a 16 mg
single dose of ondansetron hydrochloride. The Committee voted in favor
of including each drug product entry on the list as proposed by FDA.\1\
---------------------------------------------------------------------------
\1\ A transcript of the June 2015 Committee meeting (Ref. 1) and
briefing information that includes reviews and background on the
proposed entries (Ref. 2) may be found at the Dockets Management
Staff (see ADDRESSES) and at https://wayback.archive-it.org/7993/20170111202622/https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/ucm431285.htm.
---------------------------------------------------------------------------
B. The Proposed Rule
In the Federal Register of October 18, 2016, FDA proposed to revise
the withdrawn or removed list to add all drug products containing
aprotinin, all drug products containing bromocriptine mesylate for the
prevention of physiological lactation, and all intravenous drug
products containing greater than a 16 mg single dose of ondansetron
hydrochloride (October 2016 proposed rule). The addition of all drug
products containing more than 325 mg of acetaminophen per dosage unit
to the list was not included in the October 2016 proposed rule and
remains under consideration by the Agency.
C. The Final Rule
The Agency has considered the public discussion and the advice
provided by the Committee regarding these matters at the June 2015
meeting, as well as the October 2016 proposed rule, including the
comments submitted on the proposed rule (see section IV). Based on the
information before FDA and its own knowledge and expertise, FDA is
adding two entries from the proposed rule to the withdrawn or removed
list in Sec. 216.24.
The two entries FDA is adding to Sec. 216.24 are as follows:
Bromocriptine mesylate: All drug products containing bromocriptine
mesylate for prevention of physiological lactation.
Ondansetron hydrochloride: All intravenous drug products containing
greater than a 16 mg single dose of ondansetron hydrochloride.
At this time, FDA is not finalizing the entry in the proposed rule
for all drug products containing aprotinin. The addition of an entry to
the withdrawn or removed list for drug products containing aprotinin
remains under consideration by FDA.
[[Page 63571]]
IV. Comments on the Proposed Rule and FDA's Responses
Four comments, all from individuals, were submitted on the October
2016 proposed rule. FDA has summarized and responded to the relevant
comments in the following paragraphs. A comment about ``hernia repair
with mesh and plug'' has not been answered because it was not relevant
to this rulemaking. Comments regarding the proposed addition of an
entry to the withdrawn or removed list for aprotinin will not be
answered at this time because the entry remains under consideration by
FDA.
To make it easier to identify the comments and FDA's responses, the
word ``Comment,'' in parentheses, appears before the comment's
description, and the word ``Response,'' in parentheses, appears before
the Agency's response. We have numbered each comment to help
distinguish between different comments. Similar comments are grouped
together under the same number, and, in some cases, different subjects
discussed in the same comment are separated and designated as distinct
comments for purposes of FDA's response. The number assigned to each
comment or comment topic is purely for organizational purposes and does
not signify the comment's value or importance or the order in which the
comments were received.
A. Comments on Proposed Entries for Inclusion on the List
1. Bromocriptine Mesylate
(Comment 1) One comment supported the proposal to include all drug
products containing bromocriptine mesylate for prevention of
physiological lactation on the withdrawn or removed list.
(Response 1) FDA agrees with the comment.
(Comment 2) FDA received one comment opposing the proposal to
include all drug products containing bromocriptine mesylate for
prevention of physiological lactation on the withdrawn or removed list.
The comment asserts that bromocriptine mesylate offers ``significant
improvements in the quantity and quality of life,'' and, although it
has ``serious adverse effects,'' the benefits of bromocriptine mesylate
compared to its risks ``should warrant continuous approvability.''
(Response 2) FDA disagrees with the comment. For the reasons that
follow, FDA will add all drug products containing bromocriptine
mesylate for prevention of physiological lactation to the list in Sec.
216.24.
As a preliminary matter, the issue in this rulemaking is whether
all drug products containing bromocriptine mesylate for the indication
of prevention of physiological lactation were withdrawn or removed from
the market because they were found to be unsafe or not effective for
this indication. The criteria that must be met to place a drug product
on the withdrawn or removed list are laid out in the FD&C Act. Under
sections 503A and 503B of the FD&C Act, to be placed on the withdrawn
or removed list, drug products must have been withdrawn or removed from
the market because such drug products or components of such drug
products have been found to be unsafe or not effective.
As FDA previously explained in the October 2016 proposed rule, FDA
withdrew approval of PARLODEL (bromocriptine mesylate, NDA 17962) for
the indication of prevention of physiological lactation in a document
published in the Federal Register of January 17, 1995 (60 FR 3404). At
the time, PARLODEL was the only marketed drug product containing
bromocriptine mesylate labeled with this indication. FDA's 2015
``Review of Bromocriptine Mesylate for the Withdrawn or Removed List''
indicates that the 1995 withdrawal of PARLODEL for prevention of
physiological lactation was based on the unfavorable benefit-risk
balance of this product for this indication. See ``Review of
Bromocriptine Mesylate for the Withdrawn or Removed List'' in the FDA
Briefing Document for the June 17 and 18, 2015 Pharmacy Compounding
Advisory Committee Meeting, available at https://wayback.archive-it.org/7993/20170113060809/https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/ucm449533.htm. In particular, in a notice published in the Federal
Register on August 23, 1994 (59 FR 43347), FDA concluded that
bromocriptine mesylate's risks of hypertension, seizures, and
cardiovascular accidents outweighed the product's marginal benefit in
preventing postpartum lactation, which can be suppressed without risk
by using more conservative, nonpharmacological treatments. Withdrawal
of PARLODEL's indication for the prevention of physiological lactation
became effective on February 16, 1995 (60 FR 3404). FDA has determined
that all drug products containing bromocriptine mesylate for prevention
of physiological lactation were withdrawn or removed from the market
because such products have been found to be unsafe or not effective. We
note that FDA-approved drug products containing bromocriptine mesylate
for other indications, such as treatment of Parkinson's disease,
acromegaly, and prolactin-secreting adenomas, remain marketed.
FDA's 2015 review, which included a discussion of the withdrawal of
PARLODEL's indication for the prevention of physiological lactation,
was presented to the Committee at the meeting held on June 17 and 18,
2015, and the Committee voted in favor of the Agency's proposal to
include all drug products containing bromocriptine mesylate for the
prevention of physiological lactation on the list. For these reasons,
FDA proposed in the October 2016 proposed rule to include all drug
products containing bromocriptine mesylate for the prevention of
physiological lactation on the withdrawn or removed list.
The comment offered no scientific rationale or support for its
position that this drug product should not be on the list; therefore,
FDA is including bromocriptine mesylate for prevention of physiological
lactation on the withdrawn or removed list.
2. Ondansetron Hydrochloride
(Comment 3) One comment supported the proposal to include all
intravenous drug products containing greater than a 16 mg single dose
of ondansetron hydrochloride on the withdrawn or removed list.
(Response 3) FDA agrees with the comment.
(Comment 4) FDA received one comment on the proposal to include all
intravenous drug products containing greater than a 16 mg single dose
of ondansetron hydrochloride suggesting ``perhaps there is more to
investigate and stricter regulation of the administration of IV
ondansetron hydrochloride is warranted in the future.''
(Response 4) FDA intends to monitor future approvals, withdrawals,
or removals of drugs, to consider other relevant information that may
suggest the need to revise the withdrawn or removed list, and to
propose modifications as appropriate. In addition, members of the
public can submit a citizen petition at any time under 21 CFR 10.25 and
10.30 requesting that FDA add, modify, or remove an entry on the list
(with data to support their request), and FDA will consider and respond
to the petition.
(Comment 5) FDA received one comment opposing the proposal to
include all intravenous drug products containing greater than a 16 mg
single dose of ondansetron hydrochloride on
[[Page 63572]]
the withdrawn or removed list. The comment asserts that ondansetron
hydrochloride offers ``significant improvements in the quantity and
quality of life,'' and, although it has ``serious adverse effects,''
the benefits of ondansetron hydrochloride compared to its risks
``should warrant continuous approvability.''
(Response 5) FDA disagrees with the comment. For the reasons that
follow, FDA will add all intravenous drug products containing greater
than a 16 mg single dose of ondansetron hydrochloride to the list in
Sec. 216.24.
As noted earlier, the issue in this rulemaking is whether drug
products containing greater than a 16 mg single dose of ondansetron
hydrochloride were withdrawn or removed from the market because they
were found to be unsafe or not effective.
As FDA previously explained in the October 2016 proposed rule, in
the Federal Register of June 10, 2015 (80 FR 32962), FDA announced its
determination under 21 CFR 314.161 and 314.162(a)(2) that the NDA for
Ondansetron (ondansetron hydrochloride) Injection, USP, 32 mg/50 mL,
single IV dose was withdrawn from sale for reasons of safety. In
particular, this product was associated with a specific type of
irregular heart rhythm called QT interval prolongation, and the data
suggest that any dose above the maximum recommendation of 16 mg per
dose intravenously has the potential for increased risk of QT
prolongation. FDA made this determination after holders of one NDA and
four ANDAs voluntarily removed such products from the market and
requested that FDA withdraw approval of their respective applications
under 21 CFR 314.150(d). Thus, all drug products containing greater
than a 16 mg single dose of ondansetron hydrochloride have been
withdrawn or removed from the market because such drug products have
been found to be unsafe or not effective. We note that FDA-approved
drug products containing lower single doses of ondansetron
hydrochloride remain marketed.
FDA's review of intravenous drug products containing greater than a
16 mg single dose of ondansetron hydrochloride was presented to the
Committee at the meeting held on June 17 and 18, 2015, and the
Committee voted in favor of the Agency's proposal to include all
intravenous drug products containing greater than a 16 mg single dose
of ondansetron hydrochloride on the list. For these reasons, FDA
proposed in the October 2016 proposed rule to include all intravenous
drug products containing greater than a 16 mg single dose of
ondansetron hydrochloride on the withdrawn or removed list.
(Comment 6) FDA received one comment asserting that ondansetron
hydrochloride should not be recommended for use by pregnant women
because it was not approved by FDA for pregnant women.
(Response 6) This comment is outside the scope of this rulemaking.
Compounded drugs are not FDA approved and this rulemaking addresses the
placement of certain drug products on the withdrawn or removed list,
including all intravenous drug products containing greater than a 16 mg
single dose of ondansetron hydrochloride. As previously noted, drugs
appearing on this list may not be compounded under the exemptions
provided by sections 503A and 503B of the FD&C Act. Therefore, to the
extent the commenter believes that intravenous drug products containing
greater than a 16 mg single dose of ondansetron hydrochloride should
not be compounded for pregnant women under the exemptions provided by
sections 503A and 503B of the FD&C Act, we agree. The addition of the
entry FDA is finalizing regarding ondansetron hydrochloride through
this rulemaking for the list in Sec. 216.24 will prohibit compounding
of intravenous drug products containing greater than a 16 mg single
dose of ondansetron hydrochloride under the exemptions provided by
sections 503A and 503B of the FD&C Act for all patients, including
pregnant women.
V. Legal Authority
Sections 503A and 503B of the FD&C Act provide the principal legal
authority for this final rule. As described previously in section II,
section 503A of the FD&C Act describes the conditions that must be
satisfied for human drug products compounded by a licensed pharmacist
or licensed physician to be exempt from three sections of the FD&C Act
(sections 501(a)(2)(B), 502(f)(1), and 505). One of the conditions that
must be satisfied to qualify for the exemptions under section 503A of
the FD&C Act is that the licensed pharmacist or licensed physician does
not compound a drug product that appears on a list published by FDA in
the Federal Register of drug products that have been withdrawn or
removed from the market because such drug products or components of
such drug products have been found to be unsafe or not effective (see
section 503A(b)(1)(C) of the FD&C Act). Section 503A(c)(1) of the FD&C
Act also states that the Secretary shall issue regulations to implement
section 503A, and that before issuing regulations to implement section
503A(b)(1)(C) pertaining to the withdrawn or removed list, among other
sections, the Secretary shall convene and consult an advisory committee
on compounding unless the Secretary determines that the issuance of
such regulations before consultation is necessary to protect the public
health.\2\
---------------------------------------------------------------------------
\2\ Note: The functions of the Secretary described herein have
been delegated to FDA.
---------------------------------------------------------------------------
Section 503B of the FD&C Act describes the conditions that must be
satisfied for a drug compounded for human use by or under the direct
supervision of a licensed pharmacist in an outsourcing facility to be
exempt from three sections of the FD&C Act (sections 502(f)(1), 505,
and 582). One of the conditions in section 503B of the FD&C Act that
must be satisfied to qualify for the exemptions is that the drug does
not appear on a list published by FDA of drugs that have been withdrawn
or removed from the market because such drugs or components of such
drugs have been found to be unsafe or not effective (see section
503B(a)(4)). To be eligible for the exemptions in section 503B, a drug
must be compounded in an outsourcing facility in which the compounding
of drugs occurs only in accordance with section 503B, including as
provided in section 503B(a)(4) of the FD&C Act.
Thus, sections 503A and 503B of the FD&C Act, in conjunction with
our general rulemaking authority in section 701(a) of the FD&C Act (21
U.S.C. 371(a)), serve as our principal legal authority for this final
rule revising FDA's regulation on the list of drug products withdrawn
or removed from the market because such drug products or components of
such drug products have been found to be unsafe or not effective in
Sec. 216.24.
VI. 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.
VII. Economic Analysis of Impacts
We have examined the impacts of the final rule under Executive
Order 12866, Executive Order 13563, Executive Order 13771, 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
[[Page 63573]]
necessary, to select regulatory approaches that maximize net benefits
(including potential economic, environmental, public health and safety,
and other advantages; distributive impacts; and equity). Executive
Order 13771 requires that the costs associated with significant new
regulations ``shall, to the extent permitted by law, be offset by the
elimination of existing costs associated with at least two prior
regulations.'' This final rule is not a significant regulatory action
as defined by Executive Order 12866 and is not subject to Executive
Order 13771.
The Regulatory Flexibility Act requires us to analyze regulatory
options that would minimize any significant impact of a rule on small
entities. Because small businesses are not expected to incur any
compliance costs or loss of sales due to this regulation, we certify
that the final 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 issuing ``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 $150
million, using the most current (2017) Implicit Price Deflator for the
Gross Domestic Product. This final rule is not expected to result in an
expenditure in any year that would meet or exceed this amount.
This final rule amends Sec. 216.24 concerning human drug
compounding. Specifically, the final rule adds to the list of drug
products that may not be compounded under the exemptions provided by
sections 503A and 503B of the FD&C Act because the drug products have
been withdrawn or removed from the market because such drug products or
components of such drug products have been found to be unsafe or not
effective (see section II). We are adding two entries to the list: Drug
products containing bromocriptine mesylate for prevention of
physiological lactation and intravenous drug products containing
greater than a 16 mg single dose of ondansetron hydrochloride. The
Agency is not aware of routine compounding of these drug products;
therefore, we do not estimate any compliance costs or loss of sales as
a result of the prohibition against compounding these drugs for human
use.
Unless we certify that a rule will not have a significant economic
impact on a substantial number of small entities, the Regulatory
Flexibility Act requires us to analyze regulatory options to minimize
any significant economic impact of a regulation on small entities. Most
pharmacies meet the Small Business Administration definition of a small
entity, which is defined as having annual sales less than $27.5 million
for this industry. We are not aware of any routine compounding of the
drug products that are the subject of this final rule and do not
estimate any compliance costs or loss of sales to small businesses as a
result of the prohibition against compounding these drug products.
Therefore, we certify that this final rule will not have a significant
economic impact on a substantial number of small entities.
VIII. Paperwork Reduction Act of 1995
This final rule contains no collections of information. Therefore,
clearance by the Office of Management and Budget under the Paperwork
Reduction Act of 1995 is not required.
IX. Consultation and Coordination With Indian Tribal Governments
We have analyzed this rule in accordance with the principles set
forth in Executive Order 13175. We have determined that the rule does
not contain policies that have substantial direct effects on one or
more Indian Tribes, on the relationship between the Federal Government
and Indian Tribes, or on the distribution of power and responsibilities
between the Federal Government and Indian Tribes. Accordingly, we
conclude that the rule does not contain policies that have tribal
implications as defined in the Executive Order and, consequently, a
tribal summary impact statement is not required.
X. Federalism
We have analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. FDA has determined that the final
rule does not contain policies that have substantial direct effects on
the States, on the relationship between the National Government and the
States, or on the distribution of power and responsibilities among the
various levels of government. Accordingly, the Agency concludes 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.
XI. References
The following references are on display in the Dockets Management
Staff (see ADDRESSES) and are available for viewing by interested
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also
available electronically at https://www.regulations.gov. FDA has
verified the website addresses, as of the date this document publishes
in the Federal Register, but websites are subject to change over time.
1. Transcript for the June 17-18, 2015, Meeting of the Pharmacy
Compounding Advisory Committee, available at https://wayback.archive-it.org/7993/20170111202622/https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/ucm431285.htm.
2. Briefing Information for the June 17-18, 2015, Meeting of the
Pharmacy Compounding Advisory Committee, available at https://wayback.archive-it.org/7993/20170111202622/https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/ucm431285.htm.
List of Subjects in 21 CFR Part 216
Drugs, Prescription drugs.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
216 is amended as follows:
PART 216--HUMAN DRUG COMPOUNDING
0
1. The authority citation for part 216 continues to read as follows:
Authority: 21 U.S.C. 351, 352, 353a, 353b, 355, and 371.
0
2. Amend Sec. 216.24 by adding, in alphabetical order, to the list of
drugs ``Bromocriptine mesylate'' and ``Ondansetron hydrochloride'' to
read as follows:
Sec. 216.24 Drug products withdrawn or removed from the market for
reasons of safety or effectiveness.
* * * * *
Bromocriptine mesylate: All drug products containing bromocriptine
mesylate for prevention of physiological lactation.
* * * * *
Ondansetron hydrochloride: All intravenous drug products containing
greater than a 16 milligram single dose of ondansetron hydrochloride.
* * * * *
[[Page 63574]]
Dated: December 4, 2018.
Scott Gottlieb,
Commissioner of Food and Drugs.
[FR Doc. 2018-26712 Filed 12-10-18; 8:45 am]
BILLING CODE 4164-01-P
