Document ID: FDA-2016-N-2462-0001
Agency: fda
Document Type: Proposed Rule
Title: 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That Have Been Withdrawn or Removed From the Market for Reasons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
Posted Date: 2016-10-18T04:00Z

[Federal Register Volume 81, Number 201 (Tuesday, October 18, 2016)]
[Proposed Rules]
[Pages 71648-71653]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[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That Have Been Withdrawn or Removed From the Market for Reasons of 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that have been withdrawn or removed from the market because the drug 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