81_FR_71849 81 FR 71648 - Amendments to the Regulation Regarding the List of Drug Products That Have Been Withdrawn or Removed From the Market for Reasons of Safety or Effectiveness

81 FR 71648 - Amendments to the Regulation Regarding the List of Drug Products That Have Been Withdrawn or Removed From the Market for Reasons of Safety or Effectiveness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(FDA or the Agency) is proposing to amend its regulations to revise the list of drug products that have been withdrawn or removed from the market because the drug products or components of such drug products have been found to be unsafe or not effective.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That Have Been Withdrawn or Removed From the Market for Reasons of 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that have been withdrawn or removed from the market because the drug 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/ VerDate Sep<11>2014 12:33 Oct 17, 2016 Jkt 241001 PO 00000 Frm 00005 Fmt 4702 Sfmt 4702 E:\FR\FM\18OCP1.SGM 18OCP1

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 VerDate Sep<11>2014 12:33 Oct 17, 2016 Jkt 241001 PO 00000 Frm 00006 Fmt 4702 Sfmt 4702 E:\FR\FM\18OCP1.SGM 18OCP1

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 VerDate Sep<11>2014 12:33 Oct 17, 2016 Jkt 241001 PO 00000 Frm 00007 Fmt 4702 Sfmt 4702 E:\FR\FM\18OCP1.SGM 18OCP1

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 VerDate Sep<11>2014 12:33 Oct 17, 2016 Jkt 241001 PO 00000 Frm 00008 Fmt 4702 Sfmt 4702 E:\FR\FM\18OCP1.SGM 18OCP1

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. VerDate Sep<11>2014 12:33 Oct 17, 2016 Jkt 241001 PO 00000 Frm 00009 Fmt 4702 Sfmt 4702 E:\FR\FM\18OCP1.SGM 18OCP1

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. VerDate Sep<11>2014 12:33 Oct 17, 2016 Jkt 241001 PO 00000 Frm 00010 Fmt 4702 Sfmt 4702 E:\FR\FM\18OCP1.SGM 18OCP1


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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