81_FR_71849 81 FR 71648 - Amendments to the Regulation Regarding the List of Drug Products That Have Been Withdrawn or Removed From the Market for Reasons of Safety or Effectiveness

81 FR 71648 - Amendments to the Regulation Regarding the List of Drug Products That Have Been Withdrawn or Removed From the Market for Reasons of Safety or Effectiveness

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration

Federal Register Volume 81, Issue 201 (October 18, 2016)

Page Range71648-71653
FR Document2016-25005

The Food and Drug Administration (FDA or the Agency) is proposing to amend its regulations to revise the list of drug products that have been withdrawn or removed from the market because the drug products or components of such drug products have been found to be unsafe or not effective. Drugs 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 (the FD&C Act). Specifically, the proposed rule would add three entries to this list of drug products.

Federal Register, Volume 81 Issue 201 (Tuesday, October 18, 2016)
[Federal Register Volume 81, Number 201 (Tuesday, October 18, 2016)]
[Proposed Rules]
[Pages 71648-71653]
From the Federal Register Online  [www.thefederalregister.org]
[FR Doc No: 2016-25005]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 216

[Docket No. FDA-2016-N-2462]


Amendments to the Regulation Regarding the 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That Have Been Withdrawn or Removed From the Market for Reasons of 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: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA or the Agency) is 
proposing to amend its regulations to revise the list of drug products 
that have been withdrawn or removed from the market because the drug 
products or components of such drug products have been found to be 
unsafe or not effective. Drugs 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 (the FD&C Act). Specifically, 
the proposed rule would add three entries to this list of drug 
products.

DATES: Submit either electronic or written comments on the proposed 
rule by January 3, 2017.

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-2016-N-2462 for ``Amendments to the Regulation Regarding the List 
of Drug Products That Have Been Withdrawn or Removed From the Market 
for Reasons of Safety or Effectiveness.'' 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.fda.gov/

[[Page 71649]]

regulatoryinformation/dockets/default.htm.
    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: Edisa Gozun, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 5199, 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 Proposed Regulatory 
Action
    C. 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. Description of the Proposed Rule
IV. Legal Authority
V. Analysis of Environmental Impact
VI. Economic Analysis of Impacts
VII. Paperwork Reduction Act of 1995
VIII. Federalism
IX. References

I. Executive Summary

A. Purpose of the Regulatory Action

    FDA is proposing to amend its regulations to revise the list of 
drug products that have been withdrawn or removed from the market 
because the 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)). Drugs 
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).
    The Agency is proposing to add three entries (all drug products 
containing aprotinin, all drug products containing bromocriptine 
mesylate, and all intravenous drug products containing greater than a 
16 milligram (mg) single dose of ondansetron hydrochloride) as 
described in this document to the list in Sec.  216.24 of drug products 
that cannot be compounded for human use under the exemptions provided 
by either section 503A or 503B of the FD&C Act because they 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.

B. Summary of the Major Provisions of the Proposed Regulatory Action

    We are proposing that the following drugs that have been withdrawn 
or removed from the market because such drug products have been found 
to be unsafe or not effective be added to the list in Sec.  216.24. The 
specific entries proposed for addition to the list for each of these 
drugs are provided as follows:
    Aprotinin: All drug products containing aprotinin.
    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.

C. Costs and Benefits

    The Agency is not aware of any routine use of the drug products 
that FDA is proposing to add to the the withdrawn or removed list and, 
therefore, does 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 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 to qualify for the 
exemptions under both sections 503A and 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 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 
(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 Sec.  216.24 (the withdrawn or removed 
list) have been withdrawn or removed from the market because they have 
been found to be unsafe or not effective and are ineligible for the 
exemptions set forth in sections 503A and 503B of the FD&C Act. A drug 
product that is included in the list codified at Sec.  216.24 is not 
eligible for the exemptions provided in section 503A(a) of the FD&C 
Act, and is subject to sections 501(a)(2)(B), 502(f)(1), and 505 of the 
FD&C Act, in addition to other applicable provisions, if compounded. In 
addition, a drug that is included in the list codified at Sec.  216.24 
cannot qualify for the exemptions provided in section 503B(a) of the 
FD&C Act, and is subject to sections 502(f)(1), 505, and 582 of the 
FD&C Act, in addition to other applicable provisions, if compounded.

C. Regulatory History of the List

    Following the addition of section 503A to the FD&C Act on November 
21, 1997, through the enactment of the Food and Drug Administration 
Modernization Act of 1997 (Pub. L. 105-115), FDA proposed a rule in the 
Federal Register of October 8, 1998 (63 FR 54082), to establish the 
original list of drug products that have been withdrawn or removed from 
the market because the drug products or the components of such drug 
products have been found to be unsafe or not effective (1998 proposed 
rule) and therefore were not permitted to be compounded for human use 
under the exemptions provided by section 503A(a).
    In the Federal Register of March 8, 1999 (64 FR 10944), FDA 
published a final rule that codified the original list in Sec.  216.24 
(1999 final rule).
    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 proposed to amend 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

[[Page 71650]]

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, FDA revised and updated the list at Sec.  216.24 to 
clarify that it applies for purposes of both sections 503A and 503B.

III. Description of the Proposed Rule

    FDA is proposing to amend Sec.  216.24 to add three drug products, 
described in the following paragraphs, 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.
    As with the 1999 final rule establishing the original list, and the 
2016 final rule revising that list, the primary focus of this proposed 
rule is on drug products that have been withdrawn or removed from the 
market because they have been found to be unsafe. FDA may propose at a 
later date to add other drug products to the list that have been 
withdrawn or removed from the market because they have been found to be 
not effective, or to update the list as new information becomes 
available to the Agency regarding products that were removed from the 
market because they have been found to be unsafe.
    The following drugs proposed for inclusion in Sec.  216.24 are 
arranged alphabetically by the established names of the active 
ingredients contained in the 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. For 
some of the drug products, the proprietary or trade names of some or 
all of the drug products that contained the active ingredient are also 
given in the preamble paragraphs describing the withdrawn or removed 
drug products. In some cases, the withdrawn or removed drug products 
are identified according to the established name of the active 
ingredient, listed as a particular salt or ester of the active moiety. 
The following list includes the specific drug entry FDA is proposing to 
add to Sec.  216.24, as well as a brief summary of the reasons why each 
drug is being proposed for inclusion.
    a. Aprotinin: All drug products containing aprotinin.
    Bayer suspended marketing of aprotinin (TRASYLOL, NDA 20304) in 
November 2007 for safety reasons. TRASYLOL, NDA 20304, was approved on 
December 29, 1993. The indication for TRASYLOL, NDA 20304, was for 
``prophylactic use to reduce perioperative blood loss and the need for 
blood transfusion in patients undergoing cardiopulmonary bypass in the 
course of coronary artery bypass graft surgery who are at increased 
risk for blood loss and blood transfusion.'' Prominent known adverse 
reactions associated with the use of the drug included anaphylactic 
reactions (with some deaths reported) and impaired renal function. In 
January 2006, Mangano et al. published a report that described the 
results from a retrospective analysis of the use of aprotinin compared 
to two other antifibrinolytic drugs (tranexamic acid and aminocaproic 
acid) or no antifibrinolytic drugs in 4,374 patients undergoing cardiac 
surgery (Ref. 1). The conclusions were that there was a statistically 
greater likelihood of the development of renal dysfunction and the need 
for hemodialysis, stroke, encephalopathy, myocardial infarction, and 
congestive heart failure in patients treated with aprotinin than with 
the other antifibrinolytic drugs or no antifibrinolytic drugs. On 
February 8, 2006, FDA issued a Public Health Advisory on TRASYLOL, NDA 
20304, that called attention to this new information (Ref. 2). On 
September 21, 2006, FDA convened a meeting of its Cardiovascular and 
Renal Advisory Committee to evaluate these and other data for the drug 
(see http://www.fda.gov/ohrms/dockets/ac/cder07.htm#CardiovascularRenal 
for meeting documents from the September 21, 2006, Cardiovascular and 
Renal Advisory Committee meeting). The Cardiovascular and Renal 
Advisory Committee voted that the benefits of TRASYLOL, NDA 20304, 
compared to its risks warranted continued approvability for the 
indication (Yes, 18; No, 0; Abstain, 1). Before the advisory committee 
meeting, the sponsor had funded a study that evaluated a medical 
database for the outcomes of patients undergoing coronary artery bypass 
graft surgery (CABG) treated with aprotinin or other antifibrinolytics, 
which concluded that there was an increased risk of in-hospital death 
in the aprotinin-treated patients compared to those in patients treated 
with aminocaproic acid. This information was subsequently published in 
2008 by Schneeweiss et al. (Ref. 3). In 2007, Mangano et al. published 
a report in 3,876 patients undergoing CABG surgery describing a higher 
mortality after 5 years for those treated with aprotinin compared to 
those treated with no antifibrinolytic drugs (Ref. 4). In the 2007 
Mangano study, patients treated with either tranexamic acid or 
aminocaproic acid did not experience a higher mortality at 5 years 
compared to patients treated with no antifibrinolytic drug. These data 
led to a reconvening of the Cardiovascular and Renal Advisory Committee 
in a joint meeting with the Drug Safety and Risk Management Advisory 
Committee on September 12, 2007 (joint meeting), at which these and 
other data were reviewed (see http://www.fda.gov/ohrms/dockets/ac/cder07.htm#CardiovascularRenal for meeting documents from the September 
12, 2007, Cardiovascular and Renal Advisory Committee meeting). The 
Committees at the joint meeting were informed that there was an ongoing 
prospective randomized trial of aprotinin, tranexamic acid, and 
aminocaproic acid in patients undergoing CABG surgery with 
cardiopulmonary bypass in Canada (named the BART study), but that the 
results would not be available for several years. Some of the Committee 
members at the joint meeting stated that the issue should be revisited 
once the data from the BART study were available. The Advisory 
Committees at the joint meeting voted that TRASYLOL, NDA 20304, should 
continue to be authorized to be marketed in the United States. Shortly 
after the joint meeting, FDA was informed that the Data Monitoring and 
Safety Committee for the BART study had recommended that the BART trial 
be terminated early because there appeared to be a greater frequency of 
death in patients treated with aprotinin (6.0 percent) compared to 
those treated in the combined tranexamic acid plus aminocaproic acid 
group (3.9 percent). The study was subsequently published in 2008 by 
Fergusson (Ref. 5). On October 25, 2007, FDA issued a Safety Alert for 
Human Medical Products alerting the medical community about the 
preliminary data from the BART trial (Ref. 6). On November 5, 2007, FDA 
issued a press release stating that, at the Agency's request, the 
sponsor had made a decision to suspend the marketing of TRASYLOL, NDA 
20304, pending a review of the BART data for safety (Ref. 7). Although 
some of the data from the BART trial were submitted to FDA and the 
sponsor submitted its analysis of the data that was made available to 
the company, FDA was never successful in obtaining the raw data from 
the trial. Therefore, FDA was not able to conduct its own analyses of 
the trial data. TRASYLOL, NDA 20304, has not returned to the U.S. 
market since the sponsor announced its decision to suspend marketing in 
2007. Aprotinin was made available by the sponsor for the treatment of 
certain surgical patients with an established medical need using

[[Page 71651]]

a treatment protocol under an investigational new drug application 
(IND) (Ref. 8). Expanded access to aprotinin through this treatment 
protocol is no longer available (see https://clinicaltrials.gov/ct2/show/NCT00611845?term=aprotinin&rank=4). FDA is not aware of any data 
that would give us reason to believe that the safety issues identified 
as having been associated with aprotinin should be restricted to a 
particular formulation, concentration, indication, route of 
administration, or dosage form. For these reasons, FDA is proposing to 
include all drug products containing aprotinin on the withdrawn or 
removed list.
    b. Bromocriptine mesylate: All drug products containing 
bromocriptine mesylate for prevention of physiological lactation.
    Bromocriptine mesylate was associated with risks of hypertension, 
seizures, and cardiovascular accidents, and the unfavorable benefit-
risk balance was specific to the use of bromocriptine mesylate for the 
prevention of physiological lactation. In 1980, PARLODEL (bromocriptine 
mesylate) was approved for the prevention of physiological lactation as 
an acceptable alternative to estrogenic therapy. Subsequently, FDA 
received postmarket reports of serious and life-threatening adverse 
reactions (hypertension, seizures, and cerebrovascular accidents) 
associated with the use of bromocriptine mesylate to suppress 
lactation. According to the approved labeling for PARLODEL, dated July 
15, 1988 (Ref. 9), serious adverse reactions reported in postpartum 
women included 50 cases of hypertension, 38 cases of seizures 
(including 4 cases of status epilepticus), 15 cases of strokes, and 3 
cases of myocardial infarction. These cases were discussed at a 1989 
Fertility and Maternal Health Drugs Advisory Committee meeting (Ref. 
10). FDA presented reports of its safety findings, which included 28 
reports of hypertension, 36 reports of seizures, and 19 reports of 
cerebrovascular accidents. FDA had received 85 cases of serious adverse 
events, including 10 deaths, since the approval of bromocriptine 
mesylate for lactation suppression in 1980 (August 23, 1994 (59 FR 
43347)). The Fertility and Maternal Health Drugs Advisory Committee 
recommended that no drug then labeled for lactation suppression 
including bromocriptine mesylate be used for this indication. FDA 
subsequently asked that all manufacturers of these drugs voluntarily 
remove this indication from drug labeling. All but Sandoz, the 
manufacturer of PARLODEL, complied with FDA's request. In a document 
published in the Federal Register of August 23, 1994, FDA concluded 
that the risks of hypertension, seizures, and cardiovascular accidents 
outweighed the product's marginal benefit in preventing postpartum 
lactation. Accordingly, FDA proposed to withdraw approval of the 
indication recommending bromocriptine mesylate for preventing 
physiological lactation in the NDA for PARLODEL, under section 505(e) 
of the FD&C Act, on the basis that the drug is no longer shown to be 
safe for this indication. FDA withdrew approval of PARLODEL for the 
indication of prevention of physiological lactation in a document 
published in the Federal Register of January 17, 1995 (60 FR 3404). 
Withdrawal of PARLODEL's indication for the prevention of physiological 
lactation became effective on February 16, 1995. FDA's review of the 
withdrawal indicates that the withdrawal of bromocriptine mesylate for 
prevention of physiological lactation was fundamentally based on an 
unfavorable benefit-risk balance specific to this indication and not to 
other approved indications (such as treatment of Parkinson's disease, 
acromegaly, and prolactin-secreting adenomas). For this reason, FDA is 
proposing to include all drug products containing bromocriptine 
mesylate for prevention of physiological lactation on the withdrawn or 
removed list.
    c. Ondansetron hydrochloride: All intravenous drug products 
containing greater than a 16 mg single dose of ondansetron 
hydrochloride.
    Ondansetron (ondansetron hydrochloride (HCl)) Injection, USP, 32 
mg, in 50 milliliters (mL), single intravenous (IV) dose, 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. In September 2011, FDA 
issued a Drug Safety Communication noting concerns that the 32 mg 
single IV dose of ZOFRAN (ondansetron HCl) and generic versions of that 
product could increase the risk of abnormal changes in the electrical 
activity of the heart, which could result in a potentially fatal 
abnormal heart rhythm (Ref. 11). Based on data subsequently collected 
from a study conducted at FDA's request by ZOFRAN's sponsor, 
GlaxoSmithKline (GSK), that identified a significant QT prolongation 
effect in connection with the 32 mg single IV dose, FDA approved GSK's 
supplemental application to remove the 32 mg single IV dose information 
from the labeling for ZOFRAN and has worked with manufacturers of all 
32 mg single IV dose ondansetron HCl products to have them removed from 
the market. On June 29, 2012, FDA issued a Drug Safety Communication to 
notify health care professionals that the 32 mg single IV dose of 
ondansetron HCl, indicated for prevention of nausea and vomiting 
associated with initial and repeat courses of emetogenic cancer 
chemotherapy in adult patients, should be avoided due to the risk of QT 
interval prolongation, which can lead to Torsades de Pointes, an 
abnormal, potentially fatal heart rhythm (Ref. 12). Subsequently, FDA 
informed the holders of one NDA and four ANDAs for ondansetron HCl that 
the Agency believes that, in light of the safety concern associated 
with ondansetron HCl in the 32 mg single IV dose, these drug products 
should be removed from the market. The application holders agreed to 
voluntarily remove their respective 32 mg single IV dose ondansetron 
HCl products from the market and requested that FDA withdraw approval 
of their respective applications under 21 CFR 314.150(d). On December 
4, 2012, FDA issued an updated Drug Safety Communication alerting 
health care professionals that these products would be removed from the 
market because of their potential for serious cardiac risks (Ref. 13). 
In the Federal Register of June 10, 2015 (80 FR 32966), FDA announced 
that it was withdrawing the approval of these five applications. On the 
same day, in a different document in the Federal Register (80 FR 
32962), FDA announced its determination under 21 CFR 314.161 and 
314.162(a)(2) that the NDA for Ondansetron (ondansetron HCl) Injection, 
USP, 32 mg/50 mL, single IV dose was withdrawn from sale for reasons of 
safety. As explained in the review of ondansetron HCl 32 mg single IV 
dose for the withdrawn or removed list (see tab 5 of the FDA briefing 
document for the June 17-18, 2015, Pharmacy Compounding Advisory 
Committee, available at http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/ucm431285.htm), for those approved products for IV ondansetron HCl that 
remain on the market, the current dosage and administration 
recommendation for adults and pediatric patients (6 months to 18 years) 
is three 0.15 mg/kilogram doses, up to a maximum of 16 mg per dose, 
infused intravenously over 15 minutes, and any dose above the maximum 
recommended

[[Page 71652]]

16 mg per IV dose has the potential for increased risk of QT 
prolongation. For these reasons, FDA is proposing to include all IV 
drug products containing greater than a 16 mg single dose of 
ondansetron HCl on the withdrawn or removed list.
    On June 17, 2015, FDA presented these three proposed entries to the 
Pharmacy Compounding Advisory Committee (see the Federal Register of 
May 22, 2015 (80 FR 29717)). In addition to these three proposed 
entries, FDA presented a potential entry for all drug products 
containing more than 325 mg of acetaminophen per dosage unit to the 
Pharmacy Compounding Advisory Committee. The addition of all drug 
products containing more than 325 mg of acetaminophen per dosage unit 
to the list remains under consideration by the Agency.
    The Pharmacy Compounding Advisory Committee voted in favor of 
including each of FDA's four proposed entries on the list. Although an 
open public hearing session was scheduled at this meeting to allow 
members of the public to present their views and opinions on the 
proposed entries to the committee members and the Agency prior to the 
vote by the Pharmacy Compounding Advisory Committee, no members of the 
public signed up to participate. A transcript of the June 2015 Pharmacy 
Compounding Advisory Committee meeting and briefing information that 
includes reviews and background on the proposed entries may be found at 
the Division of Dockets Management (see ADDRESSES) and at http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/ucm431285.htm.

IV. Legal Authority

    Sections 503A and 503B of the FD&C Act provide the principal legal 
authority for this proposed rule. As described previously in the 
Background section of this document, 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 the Secretary 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 rule, 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.
    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 the Secretary 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).
    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 
proposed rule revising FDA's regulations on drug products withdrawn or 
removed from the market because the drug product or a component of the 
drug product have been found to be unsafe or not effective in Sec.  
216.24.

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. Economic Analysis of Impacts

    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 
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. Because small businesses are not expected to incur any 
compliance costs or loss of sales due to this regulation, we propose to 
certify that the proposed rule will not have a significant economic 
impact on a substantial number of small entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 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. We do not expect this 
proposed rule to result in any 1-year expenditure that would meet or 
exceed this amount.
    This proposed rule would amend Sec.  216.24 concerning human drug 
compounding. Specifically, the proposed rule would add to or modify 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 of this document). We are 
proposing to add three entries to the list. We are not aware of any 
routine compounding for human use of the drug products that are the 
subject of this proposed rule, and therefore do not estimate any 
compliance costs or loss of sales if the proposal is adopted. However, 
we invite the submission of comments and solicit current compounding 
usage data for these drug products, if they are compounded for human 
use.

[[Page 71653]]

    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 $25.5 million 
for this industry. We are not aware of any routine compounding of these 
drug products 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 propose to certify that this 
proposed rule will not have a significant economic impact on a 
substantial number of small entities.

VII. 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.

VIII. 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.

IX. References

    The following references are on display in the Division of Dockets 
Management (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 http://www.regulations.gov. FDA has 
verified the Web site addresses, as of the date this document publishes 
in the Federal Register, but Web sites are subject to change over time.

1. Mangano, D.T., I.C. Tudor, and C. Dietzel, ``The Risk Associated 
With Aprotinin in Cardiac Surgery,'' New England Journal of 
Medicine, 354(4):353-365, 2006.
2. FDA News Release, ``FDA Issues Public Health Advisory for 
Trasylol'' (February 8, 2006), available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108592.htm.
3. Schneeweiss, S., J.D. Seeger, J. Landon, and A.M. Walker, 
``Aprotinin During Coronary-Artery Bypass Grafting and Risk of 
Death,'' New England Journal of Medicine, 358:771-783, 2008.
4. Mangano, D.T., Y. Miao, A. Vuylsteke, et al., ``Mortality 
Associated With Aprotinin During 5 Years Following Coronary Artery 
Bypass Graft Surgery,'' Journal of the American Medical Association, 
297(5):471-479, 2007.
5. Fergusson, D.A., P.C. H[eacute]bert, C.D. Mazer, et al., ``A 
Comparison of Aprotinin and Lysine Analogues in High-Risk Cardiac 
Surgery,'' New England Journal of Medicine, 358(22):2319-2331, 2008.
6. FDA Alert--Aprotinin Injection (Marketed as Trasylol) (October 
25, 2007), available at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm150815.htm.
7. FDA News Release, ``FDA Requests Marketing Suspension of 
Trasylol'' (November 5, 2007), available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm109021.htm.
8. FDA News Release, ``Manufacturer Removes Remaining Stocks of 
Trasylol Access Limited to Investigational Use'' (May 14, 2008), 
available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116895.htm.
9. FDA-PARLODEL (bromocriptine mesylate) Information, available at 
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM449535.pdf.
10. FDA Fertility and Maternal Health Drugs Advisory Committee 
Meeting Minutes (June 1 and 2, 1989), available at http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM449535.pdf.
11. FDA Drug Safety Communication--Abnormal Heart Rhythms May Be 
Associated with Use of Zofran (Ondansetron)(September 15, 2011), 
available at http://www.fda.gov/Drugs/DrugSafety/ucm271913.htm.
12. FDA Drug Safety Communication--New Information Regarding QT 
Prolongation with Ondansetron (Zofran) (June 29, 2012), available at 
http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm.
13. FDA Drug Safety Communication--Updated Information on 32 mg 
Intravenous Ondansetron (Zofran) Dose and Pre-Mixed Ondansetron 
Products (December 4, 2012), available at http://www.fda.gov/Drugs/DrugSafety/ucm330049.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, it is 
proposed that 21 CFR part 216 be 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 ``Aprotinin'', ``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.

* * * * *
    Aprotinin: All drug products containing aprotinin.
* * * * *
    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.
* * * * *

    Dated: October 11, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-25005 Filed 10-17-16; 8:45 am]
 BILLING CODE 4164-01-P



                                               71648                 Federal Register / Vol. 81, No. 201 / Tuesday, October 18, 2016 / Proposed Rules

                                               receiving disclosure from) these state                  DEPARTMENT OF HEALTH AND                              manner detailed (see ‘‘Written/Paper
                                               rules as well as other disclosure                       HUMAN SERVICES                                        Submissions’’ and ‘‘Instructions’’).
                                               regimes. The Commission is also
                                                                                                       Food and Drug Administration                          Written/Paper Submissions
                                               interested in comments that address:
                                                  • How campaigns, parties, and other                                                                           Submit written/paper submissions as
                                               political committees, voters, and others                21 CFR Part 216                                       follows:
                                               disseminate and receive electoral                                                                                • Mail/Hand delivery/Courier (for
                                                                                                       [Docket No. FDA–2016–N–2462]
                                               information via the internet and other                                                                        written/paper submissions): Division of
                                               technologies, including any data or                     Amendments to the Regulation                          Dockets Management (HFA–305), Food
                                               experiences in purchasing, selling, or                  Regarding the List of Drug Products                   and Drug Administration, 5630 Fishers
                                               distributing small or character-limited                 That Have Been Withdrawn or                           Lane, Rm. 1061, Rockville, MD 20852.
                                               advertisements on Web sites, apps, and                  Removed From the Market for Reasons                      • For written/paper comments
                                               mobile devices;                                         of Safety or Effectiveness                            submitted to the Division of Dockets
                                                  • any challenges in complying with                                                                         Management, FDA will post your
                                                                                                       AGENCY:    Food and Drug Administration,              comment, as well as any attachments,
                                               the existing disclaimer rules as applied
                                                                                                       HHS.                                                  except for information submitted,
                                               to internet communications;
                                                                                                       ACTION:   Proposed rule.                              marked and identified, as confidential,
                                                  • the technological or other                                                                               if submitted as detailed in
                                               characteristics that might define a                     SUMMARY:     The Food and Drug                        ‘‘Instructions.’’
                                               ‘‘small’’ internet advertisement;                       Administration (FDA or the Agency) is                    Instructions: All submissions received
                                                  • how a disclaimer requirement or                    proposing to amend its regulations to                 must include the Docket No. FDA–
                                               exception for ‘‘small’’ internet                        revise the list of drug products that have            2016–N–2462 for ‘‘Amendments to the
                                               advertisements might be implemented;                    been withdrawn or removed from the                    Regulation Regarding the List of Drug
                                                  • the informational benefits of                      market because the drug products or                   Products That Have Been Withdrawn or
                                               disclaimers on internet communications                  components of such drug products have                 Removed From the Market for Reasons
                                               to assist voters in identifying the source              been found to be unsafe or not effective.             of Safety or Effectiveness.’’ Received
                                               of advertising so they are better ‘‘able to             Drugs appearing on this list may not be               comments will be placed in the docket
                                               evaluate the arguments to which they                    compounded under the exemptions                       and, except for those submitted as
                                               are being subjected’’; 6                                provided by sections 503A and 503B of                 ‘‘Confidential Submissions,’’ publicly
                                                  • the informational benefits of                      the Federal Food, Drug, and Cosmetic                  viewable at http://www.regulations.gov
                                               disclaimers on internet                                 Act (the FD&C Act). Specifically, the                 or at the Division of Dockets
                                               communications, including Web sites                     proposed rule would add three entries                 Management between 9 a.m. and 4 p.m.,
                                               and social media pages, to avoid voter                  to this list of drug products.                        Monday through Friday.
                                               confusion and reduce the incidence of                   DATES: Submit either electronic or                       • Confidential Submissions—To
                                               solicitations that appear to be for                     written comments on the proposed rule                 submit a comment with confidential
                                               candidates but are actually for non-                    by January 3, 2017.                                   information that you do not wish to be
                                               candidate committees; and                               ADDRESSES: You may submit comments                    made publicly available, submit your
                                                  • the extent to which the                            as follows:                                           comments only as a written/paper
                                               Commission’s consideration of                                                                                 submission. You should submit two
                                                                                                       Electronic Submissions                                copies total. One copy will include the
                                               disclaimer requirements should take
                                               into account current or anticipated                       Submit electronic comments in the                   information you claim to be confidential
                                               models of internet advertising.                         following way:                                        with a heading or cover note that states
                                                                                                         • Federal eRulemaking Portal: http://               ‘‘THIS DOCUMENT CONTAINS
                                                  The Commission also invites
                                                                                                       www.regulations.gov. Follow the                       CONFIDENTIAL INFORMATION.’’ The
                                               additional comments on any issues
                                                                                                       instructions for submitting comments.                 Agency will review this copy, including
                                               discussed in the ANPRM and is
                                                                                                       Comments submitted electronically,                    the claimed confidential information, in
                                               particularly interested in comments
                                                                                                       including attachments, to http://                     its consideration of comments. The
                                               addressing advertisements on internet-
                                                                                                       www.regulations.gov will be posted to                 second copy, which will have the
                                               enabled applications and devices (such
                                                                                                       the docket unchanged. Because your                    claimed confidential information
                                               as apps, eReaders, and wearable
                                                                                                       comment will be made public, you are                  redacted/blacked out, will be available
                                               technology). Given the speed at which
                                                                                                       solely responsible for ensuring that your             for public viewing and posted on http://
                                               technological advances are developing,
                                                                                                       comment does not include any                          www.regulations.gov. Submit both
                                               the Commission welcomes comments
                                                                                                       confidential information that you or a                copies to the Division of Dockets
                                               that address possible regulatory
                                                                                                       third party may not wish to be posted,                Management. If you do not wish your
                                               approaches that might minimize the
                                                                                                       such as medical information, your or                  name and contact information to be
                                               need for serial revisions to the
                                                                                                       anyone else’s Social Security number, or              made publicly available, you can
                                               Commission’s rules in order to adapt to
                                                                                                       confidential business information, such               provide this information on the cover
                                               new or emerging technologies.
                                                                                                       as a manufacturing process. Please note               sheet and not in the body of your
                                                 On behalf of the Commission.                          that if you include your name, contact                comments and you must identify this
                                                 Dated: October 7, 2016.                               information, or other information that                information as ‘‘confidential.’’ Any
                                               Matthew S. Petersen,                                    identifies you in the body of your                    information marked as ‘‘confidential’’
Lhorne on DSK30JT082PROD with PROPOSALS




                                               Chairman, Federal Election Commission.                  comments, that information will be                    will not be disclosed except in
                                               [FR Doc. 2016–25103 Filed 10–17–16; 8:45 am]            posted on http://www.regulations.gov.                 accordance with 21 CFR 10.20 and other
                                               BILLING CODE 6715–01–P
                                                                                                         • If you want to submit a comment                   applicable disclosure law. For more
                                                                                                       with confidential information that you                information about FDA’s posting of
                                                 6 Citizens United v. FEC, 558 U.S. 310, 368 (2010)    do not wish to be made available to the               comments to public dockets, see 80 FR
                                               (quoting First Nat’l Bank of Boston v. Bellotti, 435    public, submit the comment as a                       56469, September 18, 2015, or access
                                               U.S. 765, 792 n.32 (1978)).                             written/paper submission and in the                   the information at: http://www.fda.gov/


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                                                                     Federal Register / Vol. 81, No. 201 / Tuesday, October 18, 2016 / Proposed Rules                                          71649

                                               regulatoryinformation/dockets/                          products or components of such drug                   under both sections 503A and 503B of
                                               default.htm.                                            products have been found to be unsafe                 the FD&C Act is that the compounder
                                                  Docket: For access to the docket to                  or not effective.                                     does not compound a drug product that
                                               read background documents or the                                                                              appears on a list published by the
                                                                                                       B. Summary of the Major Provisions of
                                               electronic and written/paper comments                                                                         Secretary of drug products that have
                                                                                                       the Proposed Regulatory Action
                                               received, go to http://                                                                                       been withdrawn or removed from the
                                               www.regulations.gov and insert the                         We are proposing that the following                market because such drug products or
                                               docket number, found in brackets in the                 drugs that have been withdrawn or                     components of such drug products have
                                               heading of this document, into the                      removed from the market because such                  been found to be unsafe or not effective
                                               ‘‘Search’’ box and follow the prompts                   drug products have been found to be                   (withdrawn or removed list) (see
                                               and/or go to the Division of Dockets                    unsafe or not effective be added to the               sections 503A(b)(1)(C), 503B(a)(4), and
                                               Management, 5630 Fishers Lane, Rm.                      list in § 216.24. The specific entries                503B(a)(11) of the FD&C Act).
                                               1061, Rockville, MD 20852.                              proposed for addition to the list for each
                                                                                                       of these drugs are provided as follows:               B. The List of Drug Products in § 216.24
                                               FOR FURTHER INFORMATION CONTACT:
                                                                                                          Aprotinin: All drug products                          The drug products listed in § 216.24
                                               Edisa Gozun, Center for Drug Evaluation                 containing aprotinin.                                 (the withdrawn or removed list) have
                                               and Research, Food and Drug                                Bromocriptine mesylate: All drug                   been withdrawn or removed from the
                                               Administration, 10903 New Hampshire                     products containing bromocriptine                     market because they have been found to
                                               Ave., Bldg. 51, Rm. 5199, Silver Spring,                mesylate for prevention of physiological              be unsafe or not effective and are
                                               MD 20993–0002, 301–796–3110.                            lactation.                                            ineligible for the exemptions set forth in
                                               SUPPLEMENTARY INFORMATION:                                 Ondansetron hydrochloride: All                     sections 503A and 503B of the FD&C
                                                                                                       intravenous drug products containing                  Act. A drug product that is included in
                                               Table of Contents
                                                                                                       greater than a 16 mg single dose of                   the list codified at § 216.24 is not
                                               I. Executive Summary                                    ondansetron hydrochloride.                            eligible for the exemptions provided in
                                                  A. Purpose of the Regulatory Action                                                                        section 503A(a) of the FD&C Act, and is
                                                  B. Summary of the Major Provisions of the            C. Costs and Benefits
                                                     Proposed Regulatory Action
                                                                                                                                                             subject to sections 501(a)(2)(B),
                                                                                                         The Agency is not aware of any                      502(f)(1), and 505 of the FD&C Act, in
                                                  C. Costs and Benefits                                routine use of the drug products that
                                               II. Background                                                                                                addition to other applicable provisions,
                                                                                                       FDA is proposing to add to the the                    if compounded. In addition, a drug that
                                                  A. Relevant Provisions of the Statute
                                                  B. The List of Drug Products in § 216.24
                                                                                                       withdrawn or removed list and,                        is included in the list codified at
                                                  C. Regulatory History of the List                    therefore, does not estimate any                      § 216.24 cannot qualify for the
                                               III. Description of the Proposed Rule                   compliance costs or loss of sales as a                exemptions provided in section 503B(a)
                                               IV. Legal Authority                                     result of the prohibition against                     of the FD&C Act, and is subject to
                                               V. Analysis of Environmental Impact                     compounding these drug products for                   sections 502(f)(1), 505, and 582 of the
                                               VI. Economic Analysis of Impacts                        human use. The Agency has determined                  FD&C Act, in addition to other
                                               VII. Paperwork Reduction Act of 1995                    that this rulemaking is not a significant
                                               VIII. Federalism                                                                                              applicable provisions, if compounded.
                                                                                                       regulatory action as defined by
                                               IX. References                                          Executive Order 12866.                                C. Regulatory History of the List
                                               I. Executive Summary                                    II. Background                                           Following the addition of section
                                               A. Purpose of the Regulatory Action                                                                           503A to the FD&C Act on November 21,
                                                                                                       A. Relevant Provisions of the Statute                 1997, through the enactment of the Food
                                                  FDA is proposing to amend its                          Section 503A of the FD&C Act                        and Drug Administration Modernization
                                               regulations to revise the list of drug                  describes the conditions that must be                 Act of 1997 (Pub. L. 105–115), FDA
                                               products that have been withdrawn or                    satisfied for human drug products                     proposed a rule in the Federal Register
                                               removed from the market because the                     compounded by a licensed pharmacist                   of October 8, 1998 (63 FR 54082), to
                                               drug products or components of such                     or licensed physician to be exempt from               establish the original list of drug
                                               drug products have been found to be                     the following three sections of the FD&C              products that have been withdrawn or
                                               unsafe or not effective (referred to as                 Act: (1) Section 501(a)(2)(B) (21 U.S.C.              removed from the market because the
                                               ‘‘the withdrawn or removed list’’ or ‘‘the              351(a)(2)(B)) (concerning current good                drug products or the components of
                                               list’’) (§ 216.24 (21 CFR 216.24)). Drugs               manufacturing practice); (2) section                  such drug products have been found to
                                               appearing on the withdrawn or removed                   502(f)(1) (21 U.S.C. 352(f)(1))                       be unsafe or not effective (1998
                                               list may not be compounded under the                    (concerning the labeling of drugs with                proposed rule) and therefore were not
                                               exemptions provided by sections 503A                    adequate directions for use); and (3)                 permitted to be compounded for human
                                               and 503B of the FD&C Act (21 U.S.C.                     section 505 (21 U.S.C. 355) (concerning               use under the exemptions provided by
                                               353a and 353b).                                         the approval of drugs under new drug                  section 503A(a).
                                                  The Agency is proposing to add three                 applications (NDAs) or abbreviated new                   In the Federal Register of March 8,
                                               entries (all drug products containing                   drug applications (ANDAs)).                           1999 (64 FR 10944), FDA published a
                                               aprotinin, all drug products containing                   In addition, section 503B of the FD&C               final rule that codified the original list
                                               bromocriptine mesylate, and all                         Act describes the conditions that must                in § 216.24 (1999 final rule).
                                               intravenous drug products containing                    be satisfied for a drug compounded for                   Following the addition of section
                                               greater than a 16 milligram (mg) single                 human use by or under the direct                      503B to the FD&C Act on November 27,
                                               dose of ondansetron hydrochloride) as                   supervision of a licensed pharmacist in               2013, through the enactment of the Drug
Lhorne on DSK30JT082PROD with PROPOSALS




                                               described in this document to the list in               an outsourcing facility to be exempt                  Quality and Security Act (Pub. L. 113–
                                               § 216.24 of drug products that cannot be                from three sections of the FD&C Act: (1)              54), FDA proposed to amend the list in
                                               compounded for human use under the                      Section 502(f)(1), (2) section 505, and (3)           § 216.24 on July 2, 2014 (79 FR 37687);
                                               exemptions provided by either section                   section 582 (21 U.S.C. 360eee–1)                      FDA published the final rule to amend
                                               503A or 503B of the FD&C Act because                    (concerning drug supply chain security).              § 216.24 in the Federal Register of
                                               they have been withdrawn or removed                       One of the conditions that must be                  October 7, 2016 (81 FR 69668) (2016
                                               from the market because such drug                       satisfied to qualify for the exemptions               final rule). Given that nearly identical


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                                               71650                 Federal Register / Vol. 81, No. 201 / Tuesday, October 18, 2016 / Proposed Rules

                                               criteria apply for a drug to be included                undergoing cardiopulmonary bypass in                  patients treated with no antifibrinolytic
                                               on the list referred to in section                      the course of coronary artery bypass                  drug. These data led to a reconvening of
                                               503A(b)(1)(C) and the list referred to in               graft surgery who are at increased risk               the Cardiovascular and Renal Advisory
                                               section 503B(a)(4) of the FD&C Act, FDA                 for blood loss and blood transfusion.’’               Committee in a joint meeting with the
                                               revised and updated the list at § 216.24                Prominent known adverse reactions                     Drug Safety and Risk Management
                                               to clarify that it applies for purposes of              associated with the use of the drug                   Advisory Committee on September 12,
                                               both sections 503A and 503B.                            included anaphylactic reactions (with                 2007 (joint meeting), at which these and
                                               III. Description of the Proposed Rule                   some deaths reported) and impaired                    other data were reviewed (see http://
                                                                                                       renal function. In January 2006,                      www.fda.gov/ohrms/dockets/ac/
                                                  FDA is proposing to amend § 216.24                   Mangano et al. published a report that                cder07.htm#CardiovascularRenal for
                                               to add three drug products, described in                described the results from a                          meeting documents from the September
                                               the following paragraphs, that have been                retrospective analysis of the use of                  12, 2007, Cardiovascular and Renal
                                               withdrawn or removed from the market                    aprotinin compared to two other                       Advisory Committee meeting). The
                                               because such drug products or                           antifibrinolytic drugs (tranexamic acid               Committees at the joint meeting were
                                               components of such drug products have                   and aminocaproic acid) or no                          informed that there was an ongoing
                                               been found to be unsafe or not effective.
                                                                                                       antifibrinolytic drugs in 4,374 patients              prospective randomized trial of
                                                  As with the 1999 final rule
                                               establishing the original list, and the                 undergoing cardiac surgery (Ref. 1). The              aprotinin, tranexamic acid, and
                                               2016 final rule revising that list, the                 conclusions were that there was a                     aminocaproic acid in patients
                                               primary focus of this proposed rule is                  statistically greater likelihood of the               undergoing CABG surgery with
                                               on drug products that have been                         development of renal dysfunction and                  cardiopulmonary bypass in Canada
                                               withdrawn or removed from the market                    the need for hemodialysis, stroke,                    (named the BART study), but that the
                                               because they have been found to be                      encephalopathy, myocardial infarction,                results would not be available for
                                               unsafe. FDA may propose at a later date                 and congestive heart failure in patients              several years. Some of the Committee
                                               to add other drug products to the list                  treated with aprotinin than with the                  members at the joint meeting stated that
                                               that have been withdrawn or removed                     other antifibrinolytic drugs or no                    the issue should be revisited once the
                                               from the market because they have been                  antifibrinolytic drugs. On February 8,                data from the BART study were
                                               found to be not effective, or to update                 2006, FDA issued a Public Health                      available. The Advisory Committees at
                                               the list as new information becomes                     Advisory on TRASYLOL, NDA 20304,                      the joint meeting voted that TRASYLOL,
                                               available to the Agency regarding                       that called attention to this new                     NDA 20304, should continue to be
                                               products that were removed from the                     information (Ref. 2). On September 21,                authorized to be marketed in the United
                                               market because they have been found to                  2006, FDA convened a meeting of its                   States. Shortly after the joint meeting,
                                               be unsafe.                                              Cardiovascular and Renal Advisory                     FDA was informed that the Data
                                                  The following drugs proposed for                     Committee to evaluate these and other                 Monitoring and Safety Committee for
                                               inclusion in § 216.24 are arranged                      data for the drug (see http://                        the BART study had recommended that
                                               alphabetically by the established names                 www.fda.gov/ohrms/dockets/ac/                         the BART trial be terminated early
                                               of the active ingredients contained in                  cder07.htm#CardiovascularRenal for                    because there appeared to be a greater
                                               the drug products that have been                        meeting documents from the September                  frequency of death in patients treated
                                               withdrawn or removed from the market                    21, 2006, Cardiovascular and Renal                    with aprotinin (6.0 percent) compared
                                               because such drug products or                           Advisory Committee meeting). The                      to those treated in the combined
                                               components of such drug products have                   Cardiovascular and Renal Advisory                     tranexamic acid plus aminocaproic acid
                                               been found to be unsafe or not effective.               Committee voted that the benefits of                  group (3.9 percent). The study was
                                               For some of the drug products, the                      TRASYLOL, NDA 20304, compared to                      subsequently published in 2008 by
                                               proprietary or trade names of some or                   its risks warranted continued                         Fergusson (Ref. 5). On October 25, 2007,
                                               all of the drug products that contained                 approvability for the indication (Yes, 18;            FDA issued a Safety Alert for Human
                                               the active ingredient are also given in                 No, 0; Abstain, 1). Before the advisory               Medical Products alerting the medical
                                               the preamble paragraphs describing the                  committee meeting, the sponsor had                    community about the preliminary data
                                               withdrawn or removed drug products.                     funded a study that evaluated a medical               from the BART trial (Ref. 6). On
                                               In some cases, the withdrawn or                         database for the outcomes of patients                 November 5, 2007, FDA issued a press
                                               removed drug products are identified                    undergoing coronary artery bypass graft               release stating that, at the Agency’s
                                               according to the established name of the                surgery (CABG) treated with aprotinin                 request, the sponsor had made a
                                               active ingredient, listed as a particular               or other antifibrinolytics, which                     decision to suspend the marketing of
                                               salt or ester of the active moiety. The                 concluded that there was an increased                 TRASYLOL, NDA 20304, pending a
                                               following list includes the specific drug               risk of in-hospital death in the                      review of the BART data for safety (Ref.
                                               entry FDA is proposing to add to                        aprotinin-treated patients compared to                7). Although some of the data from the
                                               § 216.24, as well as a brief summary of                 those in patients treated with                        BART trial were submitted to FDA and
                                               the reasons why each drug is being                      aminocaproic acid. This information                   the sponsor submitted its analysis of the
                                               proposed for inclusion.                                 was subsequently published in 2008 by                 data that was made available to the
                                                  a. Aprotinin: All drug products                      Schneeweiss et al. (Ref. 3). In 2007,                 company, FDA was never successful in
                                               containing aprotinin.                                   Mangano et al. published a report in                  obtaining the raw data from the trial.
                                                  Bayer suspended marketing of                         3,876 patients undergoing CABG                        Therefore, FDA was not able to conduct
                                               aprotinin (TRASYLOL, NDA 20304) in                      surgery describing a higher mortality                 its own analyses of the trial data.
Lhorne on DSK30JT082PROD with PROPOSALS




                                               November 2007 for safety reasons.                       after 5 years for those treated with                  TRASYLOL, NDA 20304, has not
                                               TRASYLOL, NDA 20304, was approved                       aprotinin compared to those treated                   returned to the U.S. market since the
                                               on December 29, 1993. The indication                    with no antifibrinolytic drugs (Ref. 4). In           sponsor announced its decision to
                                               for TRASYLOL, NDA 20304, was for                        the 2007 Mangano study, patients                      suspend marketing in 2007. Aprotinin
                                               ‘‘prophylactic use to reduce                            treated with either tranexamic acid or                was made available by the sponsor for
                                               perioperative blood loss and the need                   aminocaproic acid did not experience a                the treatment of certain surgical patients
                                               for blood transfusion in patients                       higher mortality at 5 years compared to               with an established medical need using


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                                                                     Federal Register / Vol. 81, No. 201 / Tuesday, October 18, 2016 / Proposed Rules                                         71651

                                               a treatment protocol under an                           with FDA’s request. In a document                     information from the labeling for
                                               investigational new drug application                    published in the Federal Register of                  ZOFRAN and has worked with
                                               (IND) (Ref. 8). Expanded access to                      August 23, 1994, FDA concluded that                   manufacturers of all 32 mg single IV
                                               aprotinin through this treatment                        the risks of hypertension, seizures, and              dose ondansetron HCl products to have
                                               protocol is no longer available (see                    cardiovascular accidents outweighed                   them removed from the market. On June
                                               https://clinicaltrials.gov/ct2/show/                    the product’s marginal benefit in                     29, 2012, FDA issued a Drug Safety
                                               NCT00611845?term=aprotinin&rank=4).                     preventing postpartum lactation.                      Communication to notify health care
                                               FDA is not aware of any data that would                 Accordingly, FDA proposed to                          professionals that the 32 mg single IV
                                               give us reason to believe that the safety               withdraw approval of the indication                   dose of ondansetron HCl, indicated for
                                               issues identified as having been                        recommending bromocriptine mesylate                   prevention of nausea and vomiting
                                               associated with aprotinin should be                     for preventing physiological lactation in             associated with initial and repeat
                                               restricted to a particular formulation,                 the NDA for PARLODEL, under section                   courses of emetogenic cancer
                                               concentration, indication, route of                     505(e) of the FD&C Act, on the basis that             chemotherapy in adult patients, should
                                               administration, or dosage form. For                     the drug is no longer shown to be safe                be avoided due to the risk of QT interval
                                               these reasons, FDA is proposing to                      for this indication. FDA withdrew                     prolongation, which can lead to
                                               include all drug products containing                    approval of PARLODEL for the                          Torsades de Pointes, an abnormal,
                                               aprotinin on the withdrawn or removed                   indication of prevention of                           potentially fatal heart rhythm (Ref. 12).
                                               list.                                                   physiological lactation in a document                 Subsequently, FDA informed the
                                                  b. Bromocriptine mesylate: All drug                  published in the Federal Register of                  holders of one NDA and four ANDAs for
                                               products containing bromocriptine                       January 17, 1995 (60 FR 3404).                        ondansetron HCl that the Agency
                                               mesylate for prevention of physiological                Withdrawal of PARLODEL’s indication                   believes that, in light of the safety
                                               lactation.                                              for the prevention of physiological
                                                  Bromocriptine mesylate was                                                                                 concern associated with ondansetron
                                                                                                       lactation became effective on February                HCl in the 32 mg single IV dose, these
                                               associated with risks of hypertension,                  16, 1995. FDA’s review of the
                                               seizures, and cardiovascular accidents,                                                                       drug products should be removed from
                                                                                                       withdrawal indicates that the                         the market. The application holders
                                               and the unfavorable benefit-risk balance                withdrawal of bromocriptine mesylate
                                               was specific to the use of bromocriptine                                                                      agreed to voluntarily remove their
                                                                                                       for prevention of physiological lactation
                                               mesylate for the prevention of                                                                                respective 32 mg single IV dose
                                                                                                       was fundamentally based on an
                                               physiological lactation. In 1980,                                                                             ondansetron HCl products from the
                                                                                                       unfavorable benefit-risk balance specific
                                               PARLODEL (bromocriptine mesylate)                                                                             market and requested that FDA
                                                                                                       to this indication and not to other
                                               was approved for the prevention of                                                                            withdraw approval of their respective
                                                                                                       approved indications (such as treatment
                                               physiological lactation as an acceptable                                                                      applications under 21 CFR 314.150(d).
                                                                                                       of Parkinson’s disease, acromegaly, and
                                               alternative to estrogenic therapy.                                                                            On December 4, 2012, FDA issued an
                                                                                                       prolactin-secreting adenomas). For this
                                               Subsequently, FDA received postmarket                                                                         updated Drug Safety Communication
                                                                                                       reason, FDA is proposing to include all
                                               reports of serious and life-threatening                                                                       alerting health care professionals that
                                                                                                       drug products containing bromocriptine
                                               adverse reactions (hypertension,                                                                              these products would be removed from
                                                                                                       mesylate for prevention of physiological
                                               seizures, and cerebrovascular accidents)                lactation on the withdrawn or removed                 the market because of their potential for
                                               associated with the use of bromocriptine                list.                                                 serious cardiac risks (Ref. 13). In the
                                               mesylate to suppress lactation.                            c. Ondansetron hydrochloride: All                  Federal Register of June 10, 2015 (80 FR
                                               According to the approved labeling for                  intravenous drug products containing                  32966), FDA announced that it was
                                               PARLODEL, dated July 15, 1988 (Ref. 9),                 greater than a 16 mg single dose of                   withdrawing the approval of these five
                                               serious adverse reactions reported in                   ondansetron hydrochloride.                            applications. On the same day, in a
                                               postpartum women included 50 cases of                      Ondansetron (ondansetron                           different document in the Federal
                                               hypertension, 38 cases of seizures                      hydrochloride (HCl)) Injection, USP, 32               Register (80 FR 32962), FDA announced
                                               (including 4 cases of status epilepticus),              mg, in 50 milliliters (mL), single                    its determination under 21 CFR 314.161
                                               15 cases of strokes, and 3 cases of                     intravenous (IV) dose, was associated                 and 314.162(a)(2) that the NDA for
                                               myocardial infarction. These cases were                 with a specific type of irregular heart               Ondansetron (ondansetron HCl)
                                               discussed at a 1989 Fertility and                       rhythm called QT interval prolongation,               Injection, USP, 32 mg/50 mL, single IV
                                               Maternal Health Drugs Advisory                          and the data suggest that any dose above              dose was withdrawn from sale for
                                               Committee meeting (Ref. 10). FDA                        the maximum recommendation of 16 mg                   reasons of safety. As explained in the
                                               presented reports of its safety findings,               per dose intravenously has the potential              review of ondansetron HCl 32 mg single
                                               which included 28 reports of                            for increased risk of QT prolongation. In             IV dose for the withdrawn or removed
                                               hypertension, 36 reports of seizures, and               September 2011, FDA issued a Drug                     list (see tab 5 of the FDA briefing
                                               19 reports of cerebrovascular accidents.                Safety Communication noting concerns                  document for the June 17–18, 2015,
                                               FDA had received 85 cases of serious                    that the 32 mg single IV dose of                      Pharmacy Compounding Advisory
                                               adverse events, including 10 deaths,                    ZOFRAN (ondansetron HCl) and generic                  Committee, available at http://
                                               since the approval of bromocriptine                     versions of that product could increase               www.fda.gov/AdvisoryCommittees/
                                               mesylate for lactation suppression in                   the risk of abnormal changes in the                   CommitteesMeetingMaterials/Drugs/
                                               1980 (August 23, 1994 (59 FR 43347)).                   electrical activity of the heart, which               PharmacyCompoundingAdvisory
                                               The Fertility and Maternal Health Drugs                 could result in a potentially fatal                   Committee/ucm431285.htm), for those
                                               Advisory Committee recommended that                     abnormal heart rhythm (Ref. 11). Based                approved products for IV ondansetron
                                               no drug then labeled for lactation                      on data subsequently collected from a                 HCl that remain on the market, the
Lhorne on DSK30JT082PROD with PROPOSALS




                                               suppression including bromocriptine                     study conducted at FDA’s request by                   current dosage and administration
                                               mesylate be used for this indication.                   ZOFRAN’s sponsor, GlaxoSmithKline                     recommendation for adults and
                                               FDA subsequently asked that all                         (GSK), that identified a significant QT               pediatric patients (6 months to 18 years)
                                               manufacturers of these drugs voluntarily                prolongation effect in connection with                is three 0.15 mg/kilogram doses, up to
                                               remove this indication from drug                        the 32 mg single IV dose, FDA approved                a maximum of 16 mg per dose, infused
                                               labeling. All but Sandoz, the                           GSK’s supplemental application to                     intravenously over 15 minutes, and any
                                               manufacturer of PARLODEL, complied                      remove the 32 mg single IV dose                       dose above the maximum recommended


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                                               71652                 Federal Register / Vol. 81, No. 201 / Tuesday, October 18, 2016 / Proposed Rules

                                               16 mg per IV dose has the potential for                 components of such drug products have                 Reform Act of 1995 (Pub. L. 104–4).
                                               increased risk of QT prolongation. For                  been found to be unsafe or not effective              Executive Orders 12866 and 13563
                                               these reasons, FDA is proposing to                      (see section 503A(b)(1)(C) of the FD&C                direct us to assess all costs and benefits
                                               include all IV drug products containing                 Act). Section 503A(c)(1) of the FD&C                  of available regulatory alternatives and,
                                               greater than a 16 mg single dose of                     Act also states that the Secretary shall              when regulation is necessary, to select
                                               ondansetron HCl on the withdrawn or                     issue regulations to implement section                regulatory approaches that maximize
                                               removed list.                                           503A, and that before issuing                         net benefits (including potential
                                                  On June 17, 2015, FDA presented                      regulations to implement section                      economic, environmental, public health
                                               these three proposed entries to the                     503A(b)(1)(C) pertaining to the                       and safety, and other advantages;
                                               Pharmacy Compounding Advisory                           withdrawn or removed rule, among                      distributive impacts; and equity). We
                                               Committee (see the Federal Register of                  other sections, the Secretary shall                   believe that this proposed rule is not a
                                               May 22, 2015 (80 FR 29717)). In                         convene and consult an advisory                       significant regulatory action as defined
                                               addition to these three proposed entries,               committee on compounding unless the                   by Executive Order 12866.
                                               FDA presented a potential entry for all                 Secretary determines that the issuance                   The Regulatory Flexibility Act
                                               drug products containing more than 325                  of such regulations before consultation               requires us to analyze regulatory options
                                               mg of acetaminophen per dosage unit to                  is necessary to protect the public health.            that would minimize any significant
                                               the Pharmacy Compounding Advisory                          Section 503B of the FD&C Act                       impact of a rule on small entities.
                                               Committee. The addition of all drug                     describes the conditions that must be                 Because small businesses are not
                                               products containing more than 325 mg                    satisfied for a drug compounded for                   expected to incur any compliance costs
                                               of acetaminophen per dosage unit to the                 human use by or under the direct                      or loss of sales due to this regulation, we
                                               list remains under consideration by the                 supervision of a licensed pharmacist in               propose to certify that the proposed rule
                                               Agency.                                                 an outsourcing facility to be exempt                  will not have a significant economic
                                                  The Pharmacy Compounding                             from three sections of the FD&C Act                   impact on a substantial number of small
                                               Advisory Committee voted in favor of                    (sections 502(f)(1), 505, and 582). One of            entities.
                                               including each of FDA’s four proposed                   the conditions in section 503B of the                    Section 202(a) of the Unfunded
                                               entries on the list. Although an open                   FD&C Act that must be satisfied to
                                                                                                                                                             Mandates Reform Act of 1995 requires
                                               public hearing session was scheduled at                 qualify for the exemptions is that the
                                                                                                                                                             us to prepare a written statement, which
                                               this meeting to allow members of the                    drug does not appear on a list published
                                               public to present their views and                                                                             includes an assessment of anticipated
                                                                                                       by the Secretary of drugs that have been
                                               opinions on the proposed entries to the                                                                       costs and benefits, before proposing
                                                                                                       withdrawn or removed from the market
                                               committee members and the Agency                                                                              ‘‘any rule that includes any Federal
                                                                                                       because such drugs or components of
                                               prior to the vote by the Pharmacy                                                                             mandate that may result in the
                                                                                                       such drugs have been found to be unsafe
                                               Compounding Advisory Committee, no                                                                            expenditure by State, local, and tribal
                                                                                                       or not effective (see section 503B(a)(4)).
                                               members of the public signed up to                                                                            governments, in the aggregate, or by the
                                                                                                       To be eligible for the exemptions in
                                               participate. A transcript of the June                                                                         private sector, of $100,000,000 or more
                                                                                                       section 503B, a drug must be
                                               2015 Pharmacy Compounding Advisory                                                                            (adjusted annually for inflation) in any
                                                                                                       compounded in an outsourcing facility
                                               Committee meeting and briefing                                                                                one year.’’ The current threshold after
                                                                                                       in which the compounding of drugs
                                               information that includes reviews and                                                                         adjustment for inflation is $146 million,
                                                                                                       occurs only in accordance with section
                                               background on the proposed entries                                                                            using the most current (2015) Implicit
                                                                                                       503B, including as provided in section
                                               may be found at the Division of Dockets                                                                       Price Deflator for the Gross Domestic
                                                                                                       503B(a)(4).
                                               Management (see ADDRESSES) and at                                                                             Product. We do not expect this
                                                                                                          Thus, sections 503A and 503B of the
                                               http://www.fda.gov/Advisory                                                                                   proposed rule to result in any 1-year
                                                                                                       FD&C Act, in conjunction with our
                                               Committees/CommitteesMeeting                                                                                  expenditure that would meet or exceed
                                                                                                       general rulemaking authority in section
                                               Materials/Drugs/Pharmacy                                                                                      this amount.
                                                                                                       701(a) of the FD&C Act (21 U.S.C.
                                               CompoundingAdvisoryCommittee/                           371(a)), serve as our principal legal                    This proposed rule would amend
                                               ucm431285.htm.                                          authority for this proposed rule revising             § 216.24 concerning human drug
                                                                                                       FDA’s regulations on drug products                    compounding. Specifically, the
                                               IV. Legal Authority                                                                                           proposed rule would add to or modify
                                                                                                       withdrawn or removed from the market
                                                 Sections 503A and 503B of the FD&C                    because the drug product or a                         the list of drug products that may not be
                                               Act provide the principal legal authority               component of the drug product have                    compounded under the exemptions
                                               for this proposed rule. As described                    been found to be unsafe or not effective              provided by sections 503A and 503B of
                                               previously in the Background section of                 in § 216.24.                                          the FD&C Act because the drug products
                                               this document, section 503A of the                                                                            have been withdrawn or removed from
                                               FD&C Act describes the conditions that                  V. Analysis of Environmental Impact                   the market because such drug products
                                               must be satisfied for human drug                          We have determined under 21 CFR                     or components of such drug products
                                               products compounded by a licensed                       25.30(h) that this action is of a type that           have been found to be unsafe or not
                                               pharmacist or licensed physician to be                  does not individually or cumulatively                 effective (see section II of this
                                               exempt from three sections of the FD&C                  have a significant effect on the human                document). We are proposing to add
                                               Act (sections 501(a)(2)(B), 502(f)(1), and              environment. Therefore, neither an                    three entries to the list. We are not
                                               505). One of the conditions that must be                environmental assessment nor an                       aware of any routine compounding for
                                               satisfied to qualify for the exemptions                 environmental impact statement is                     human use of the drug products that are
                                               under section 503A of the FD&C Act is                                                                         the subject of this proposed rule, and
Lhorne on DSK30JT082PROD with PROPOSALS




                                                                                                       required.
                                               that the licensed pharmacist or licensed                                                                      therefore do not estimate any
                                               physician does not compound a drug                      VI. Economic Analysis of Impacts                      compliance costs or loss of sales if the
                                               product that appears on a list published                  We have examined the impacts of the                 proposal is adopted. However, we invite
                                               by the Secretary in the Federal Register                proposed rule under Executive Order                   the submission of comments and solicit
                                               of drug products that have been                         12866, Executive Order 13563, the                     current compounding usage data for
                                               withdrawn or removed from the market                    Regulatory Flexibility Act (5 U.S.C.                  these drug products, if they are
                                               because such drug products or                           601–612), and the Unfunded Mandates                   compounded for human use.


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                                                                     Federal Register / Vol. 81, No. 201 / Tuesday, October 18, 2016 / Proposed Rules                                               71653

                                                  Unless we certify that a rule will not                    NewsEvents/Newsroom/                             of Food and Drugs, it is proposed that
                                               have a significant economic impact on                        PressAnnouncements/2006/                         21 CFR part 216 be amended as follows:
                                               a substantial number of small entities,                      ucm108592.htm.
                                               the Regulatory Flexibility Act requires                 3. Schneeweiss, S., J.D. Seeger, J. Landon,           PART 216—HUMAN DRUG
                                                                                                            and A.M. Walker, ‘‘Aprotinin During              COMPOUNDING
                                               us to analyze regulatory options to                          Coronary-Artery Bypass Grafting and
                                               minimize any significant economic                            Risk of Death,’’ New England Journal of
                                               impact of a regulation on small entities.                                                                     ■ 1. The authority citation for part 216
                                                                                                            Medicine, 358:771–783, 2008.                     continues to read as follows:
                                               Most pharmacies meet the Small                          4. Mangano, D.T., Y. Miao, A. Vuylsteke, et
                                               Business Administration definition of a                      al., ‘‘Mortality Associated With                   Authority: 21 U.S.C. 351, 352, 353a, 353b,
                                               small entity, which is defined as having                     Aprotinin During 5 Years Following               355, and 371.
                                               annual sales less than $25.5 million for                     Coronary Artery Bypass Graft Surgery,’’
                                                                                                                                                             ■ 2. Amend § 216.24 by adding, in
                                               this industry. We are not aware of any                       Journal of the American Medical
                                                                                                            Association, 297(5):471–479, 2007.
                                                                                                                                                             alphabetical order, to the list of drugs
                                               routine compounding of these drug                                                                             ‘‘Aprotinin’’, ‘‘Bromocriptine mesylate’’,
                                                                                                       5. Fergusson, D.A., P.C. Hébert, C.D. Mazer,
                                               products and do not estimate any                             et al., ‘‘A Comparison of Aprotinin and          and ‘‘Ondansetron hydrochloride’’ to
                                               compliance costs or loss of sales to                         Lysine Analogues in High-Risk Cardiac            read as follows:
                                               small businesses as a result of the                          Surgery,’’ New England Journal of
                                               prohibition against compounding these                        Medicine, 358(22):2319–2331, 2008.               § 216.24 Drug products withdrawn or
                                               drug products. Therefore, we propose to                 6. FDA Alert—Aprotinin Injection (Marketed            removed from the market for reasons of
                                               certify that this proposed rule will not                     as Trasylol) (October 25, 2007), available       safety or effectiveness.
                                               have a significant economic impact on                        at http://www.fda.gov/Safety/MedWatch/           *     *    *     *     *
                                               a substantial number of small entities.                      SafetyInformation/SafetyAlertsfor                  Aprotinin: All drug products
                                                                                                            HumanMedicalProducts/                            containing aprotinin.
                                               VII. Paperwork Reduction Act of 1995                         ucm150815.htm.
                                                                                                       7. FDA News Release, ‘‘FDA Requests
                                                                                                                                                             *     *    *     *     *
                                                 FDA tentatively concludes that this                                                                           Bromocriptine mesylate: All drug
                                                                                                            Marketing Suspension of Trasylol’’
                                               proposed rule contains no collection of                      (November 5, 2007), available at http://         products containing bromocriptine
                                               information. Therefore, clearance by the                     www.fda.gov/NewsEvents/Newsroom/                 mesylate for prevention of physiological
                                               Office of Management and Budget under                        PressAnnouncements/2007/                         lactation.
                                               the Paperwork Reduction Act of 1995 is                       ucm109021.htm.                                   *     *    *     *     *
                                               not required.                                           8. FDA News Release, ‘‘Manufacturer                     Ondansetron hydrochloride: All
                                                                                                            Removes Remaining Stocks of Trasylol
                                               VIII. Federalism                                             Access Limited to Investigational Use’’
                                                                                                                                                             intravenous drug products containing
                                                                                                            (May 14, 2008), available at http://             greater than a 16 milligram single dose
                                                 We have analyzed this proposed rule
                                                                                                            www.fda.gov/NewsEvents/Newsroom/                 of ondansetron hydrochloride.
                                               in accordance with the principles set
                                               forth in Executive Order 13132. We                           PressAnnouncements/2008/                         *     *    *     *     *
                                                                                                            ucm116895.htm.
                                               have determined that this proposed rule                 9. FDA–PARLODEL (bromocriptine mesylate)                Dated: October 11, 2016.
                                               does not contain policies that have                          Information, available at http://                Leslie Kux,
                                               substantial direct effects on the States,                    www.fda.gov/downloads/Advisory                   Associate Commissioner for Policy.
                                               on the relationship between the                              Committees/CommitteesMeeting                     [FR Doc. 2016–25005 Filed 10–17–16; 8:45 am]
                                               National Government and the States, or                       Materials/Drugs/PharmacyCompounding
                                                                                                                                                             BILLING CODE 4164–01–P
                                               on the distribution of power and                             AdvisoryCommittee/UCM449535.pdf.
                                               responsibilities among the various                      10. FDA Fertility and Maternal Health Drugs
                                               levels of government. Accordingly, we                        Advisory Committee Meeting Minutes
                                                                                                            (June 1 and 2, 1989), available at http://       DEPARTMENT OF COMMERCE
                                               conclude that the rule does not contain
                                                                                                            www.fda.gov/downloads/Advisory
                                               policies that have federalism                                Committees/CommitteesMeeting                     United States Patent and Trademark
                                               implications as defined in the Executive                     Materials/Drugs/PharmacyCompounding              Office
                                               order and, consequently, a federalism                        AdvisoryCommittee/UCM449535.pdf.
                                               summary impact statement is not                         11. FDA Drug Safety Communication—                    37 CFR Part 42
                                               required.                                                    Abnormal Heart Rhythms May Be
                                                                                                            Associated with Use of Zofran                    [Docket No. PTO–P–2016–0029]
                                               IX. References                                               (Ondansetron)(September 15, 2011),               RIN 0651–AD10
                                                 The following references are on                            available at http://www.fda.gov/Drugs/
                                               display in the Division of Dockets                           DrugSafety/ucm271913.htm.                        Rule Recognizing Privileged
                                               Management (see ADDRESSES) and are                      12. FDA Drug Safety Communication—New
                                                                                                            Information Regarding QT Prolongation
                                                                                                                                                             Communications Between Clients and
                                               available for viewing by interested                                                                           Patent Practitioners at the Patent Trial
                                                                                                            with Ondansetron (Zofran) (June 29,
                                               persons between 9 a.m. and 4 p.m.,                           2012), available at http://www.fda.gov/          and Appeal Board
                                               Monday through Friday; they are also                         Drugs/DrugSafety/ucm310190.htm.
                                               available electronically at http://                     13. FDA Drug Safety Communication—
                                                                                                                                                             AGENCY:  Patent Trial and Appeal Board,
                                               www.regulations.gov. FDA has verified                        Updated Information on 32 mg                     United States Patent and Trademark
                                               the Web site addresses, as of the date                       Intravenous Ondansetron (Zofran) Dose            Office, U.S. Department of Commerce.
                                               this document publishes in the Federal                       and Pre-Mixed Ondansetron Products               ACTION: Proposed rule.
                                               Register, but Web sites are subject to                       (December 4, 2012), available at http://
                                                                                                            www.fda.gov/Drugs/DrugSafety/                    SUMMARY:   This proposed rule would
Lhorne on DSK30JT082PROD with PROPOSALS




                                               change over time.
                                                                                                            ucm330049.htm.                                   amend the rules of practice before the
                                               1. Mangano, D.T., I.C. Tudor, and C. Dietzel,                                                                 Patent Trial and Appeal Board to
                                                   ‘‘The Risk Associated With Aprotinin in             List of Subjects in 21 CFR Part 216
                                                   Cardiac Surgery,’’ New England Journal
                                                                                                                                                             recognize that, in connection with
                                                                                                         Drugs, Prescription drugs.                          discovery conducted in certain
                                                   of Medicine, 354(4):353–365, 2006.
                                               2. FDA News Release, ‘‘FDA Issues Public                  Therefore, under the Federal Food,                  proceedings at the United States Patent
                                                   Health Advisory for Trasylol’’ (February            Drug, and Cosmetic Act and under                      and Trademark Office (USPTO or
                                                   8, 2006), available at http://www.fda.gov/          authority delegated to the Commissioner               Office), communications between U.S.


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Document Created: 2016-10-17 23:52:51
Document Modified: 2016-10-17 23:52:51
CategoryRegulatory Information
CollectionFederal Register
sudoc ClassAE 2.7:
GS 4.107:
AE 2.106:
PublisherOffice of the Federal Register, National Archives and Records Administration
SectionProposed Rules
ActionProposed rule.
DatesSubmit either electronic or written comments on the proposed rule by January 3, 2017.
ContactEdisa Gozun, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, Rm. 5199, Silver Spring, MD 20993-0002, 301- 796-3110.
FR Citation81 FR 71648 
CFR AssociatedDrugs and Prescription Drugs

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