Federal Register / Vol. 83, No. 167 / Tuesday, August 28, 2018 / Notices 43877 

laboratories can ensure high-quality 

laboratory testing, resulting in accurate 

and reliable testing results. 

By providing an evaluation program 

to assess the ability of the laboratories 

to test for drug resistant M. tuberculosis 

strains, laboratories also have a selfassessment tool to aid in optimizing 

their skills in susceptibility testing. The 

information obtained from the 

laboratories on susceptibility practices 

and procedures is used to establish 

variables related to good performance, 

assessing training needs, and aid with 

the development of practice standards. 

Participants in this program include 

domestic clinical and public health 

laboratories. Data collection from 

laboratory participants occurs twice per 

year. The data collected in this program 

will include the susceptibility test 

results of primary and secondary drugs, 

drug concentrations, and test methods 

performed by laboratories on a set of 

performance evaluation (PE) samples. 

The PE samples are sent to participants 

twice a year. Participants also report 

demographic data such as laboratory 

type and the number of tests performed 

annually. The total estimated annual 

burden hours are 129. There is no cost 

to respondents to participate other than 

their time. 

ESTIMATED ANNUALIZED BURDEN HOURS

Type of 

respondents Form name Number of respondents 

Number of 

responses per 

respondent 

Average 

burden per 

response 

(in hours) 

Total burden 

(in hours) 

Domestic Laboratory ......................... Participant Biosafety Compliance 

Letter of Agreement.

80 1 5/60 7 

MPEP Mycobacterium tuberculosis 

Results Worksheet.

80 2 30/60 80 

Online Survey Instrument ................ 80 2 15/60 40 

MPEP Mycobacterium tuberculosis 

Minimum Inhibitory Concentration 

Results Form.

4 2 15/60 2 

Total ........................................... ........................................................... ........................ ........................ ........................ 129 

Jeffrey M. Zirger, 

Acting Chief, Information Collection Review 

Office, Office of Scientific Integrity, Office 

of the Associate Director for Science, Office 

of the Director, Centers for Disease Control 

and Prevention. 

[FR Doc. 2018–18589 Filed 8–27–18; 8:45 am] 

BILLING CODE 4163–18–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

[Docket No. FDA–2018–N–3240] 

List of Bulk Drug Substances for 

Which There is a Clinical Need Under 

Section 503B of the Federal Food, 

Drug, and Cosmetic Act 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Notice. 

SUMMARY: The Food and Drug 

Administration (FDA or Agency) is 

developing a list of bulk drug 

substances (active pharmaceutical 

ingredients) for which there is a clinical 

need (the 503B Bulks List). Drug 

products that outsourcing facilities 

compound using bulk drug substances 

on the 503B Bulks List qualify for 

certain exemptions from the Federal 

Food, Drug, and Cosmetic Act (FD&C 

Act) provided certain conditions are 

met. This notice identifies three bulk 

drug substances that FDA has 

considered and is proposing not to 

include on the list: Bumetanide, 

nicardipine hydrochloride, and 

vasopressin. Additional bulk drug 

substances nominated by the public for 

inclusion on this list are currently under 

consideration and will be the subject of 

future notices. 

DATES: Submit either electronic or 

written comments on the notice by 

October 29, 2018 to ensure that the 

Agency considers your comment on this 

notice before it begins work on a notice 

reflecting the Agency’s final decision 

about whether to include these 

substances on the 503B Bulks List. 

ADDRESSES: You may submit comments 

at any time as follows: 

Electronic Submissions 

Submit electronic comments in the 

following way: 

• Federal eRulemaking Portal: 

https://www.regulations.gov. Follow the 

instructions for submitting comments. 

Comments submitted electronically, 

including attachments, to https://

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 https://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): Dockets 

Management Staff (HFA–305), Food and 

Drug Administration, 5630 Fishers 

Lane, Rm. 1061, Rockville, MD 20852. 

• For written/paper comments 

submitted to the Dockets Management 

Staff, 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– 

2018–N–3240 for ‘‘List of Bulk Drug 

Substances For Which There Is a 

Clinical Need Under Section 503B of the 

Federal Food, Drug, and Cosmetic Act.’’ 

Received comments will be placed in 

the docket and, except for those 

submitted as ‘‘Confidential 

Submissions,’’ publicly viewable at 

https://www.regulations.gov or at the 

Dockets Management Staff between 9 


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43878 Federal Register / Vol. 83, No. 167 / Tuesday, August 28, 2018 / Notices 

1See https://www.cdc.gov/HAI/outbreaks/ 

meningitis.html. 

2See Public Law 113–54, section 102(a), 127 Stat. 

587, 587–588 (2013). Other compounders, which 

are not the subject of this notice, are regulated 

under section 503A of the FD&C Act (21 U.S.C. 

353a). These include licensed pharmacists in Statelicensed pharmacies or Federal facilities, and 

licensed physicians, who have not registered an 

outsourcing facility with FDA. Drug products 

compounded by section 503A compounders are 

exempt from sections 505 (new drug approval 

requirements), 502(f)(1) (labeling with adequate 

directions for use), and 501(a)(2)(B) (CGMP 

requirements) if the conditions of section 503A are 

met, including that compounding is based on the 

receipt of valid prescriptions for identified 

individual patients (section 503A(a)). In general, 

section 503A compounders do not register with and 

are not routinely inspected by FDA, and they are 

primarily overseen by the States. 

3Section 503B(a) of the FD&C Act. 

4Compare section 503A(a) of the FD&C Act 

(exempting drugs compounded in accordance with 

that section) with section 503B(a) of the FD&C Act 

(not providing the exemption from CGMP 

requirements). 

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 

https://www.regulations.gov. Submit 

both copies to the Dockets Management 

Staff. 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: https://www.gpo.gov/ 

fdsys/pkg/FR-2015-09-18/pdf/2015- 

23389.pdf. 

Docket: For access to the docket to 

read background documents or the 

electronic and written/paper comments 

received, go to https://

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 Dockets Management 

Staff, 5630 Fishers Lane, Rm. 1061, 

Rockville, MD 20852. 

FOR FURTHER INFORMATION CONTACT: 

Elizabeth Hankla, Center for Drug 

Evaluation and Research, Food and 

Drug Administration, 10903 New 

Hampshire Ave., Bldg. 51, Rm. 5216, 

Silver Spring, MD 20993, 301–796– 

3110. 

SUPPLEMENTARY INFORMATION: 

I. Background 

A. Drug Compounding 

Compounded drug products can serve 

an important role for patients whose 

clinical needs cannot be met by FDAapproved drug products, such as 

patients who have an allergy and need 

a medication to be made without a 

certain inactive ingredient (e.g., a dye) 

or hospital inpatients who need 

infusions of a drug combined with a 

particular diluent. However, they also 

pose a higher risk to patients than FDAapproved drugs. In 2012, contaminated 

injectable drug products that a Statelicensed compounding pharmacy 

shipped to patients and healthcare 

practitioners across the country caused 

a fungal meningitis outbreak that 

resulted in more than 60 deaths and 750 

cases of infection.1 This was the most 

serious of a long history of outbreaks 

and other serious adverse events, 

including overdoses, associated with 

contaminated, superpotent, or otherwise 

poor quality compounded drugs. 

In response to this outbreak, Congress 

enacted the Drug Quality and Security 

Act (Pub. L. 113–54), which, among 

other things, added new section 503B to 

the FD&C Act (21 U.S.C. 353b) and 

created a new category of compounders 

known as outsourcing facilities.2 Drug 

products compounded by outsourcing 

facilities in accordance with the 

conditions of section 503B are exempt 

from FDA drug approval requirements 

and the requirement that they be labeled 

with adequate directions for use. 

Because compounded drug products are 

not FDA-approved, they have not 

undergone FDA premarket review for 

safety, effectiveness, and quality. 

Although outsourcing facilities must 

comply with current good 

manufacturing practice (CGMP) 

requirements and are inspected by FDA 

according to a risk-based schedule, their 

drug products have not been determined 

to be safe or effective for conditions of 

use reflected in drug product labeling 

and lack a premarket inspection and 

finding of manufacturing quality, all of 

which are part of the drug approval 

process. Because compounded drug 

products are subject to a lower 

regulatory standard than FDA-approved 

drug products, they should only be used 

by patients whose medical needs cannot 

be met by an FDA-approved drug 

product. 

Outsourcing facilities sometimes 

compound drug products using bulk 

drug substances and other times using 

finished drug products as the starting 

materials. In general, compounding 

using bulk drug substances presents a 

greater risk to patients than 

compounding using FDA-approved drug 

products. FDA-approved drug products 

provide certain assurances not provided 

by bulk drug substances, including 

assurances associated with premarket 

review by FDA for safety, effectiveness, 

and quality. Further, using a bulk drug 

substance in compounding when an 

FDA-approved drug product would be 

suitable would undermine the 

premarket approval process by reducing 

the incentive for applicants to invest in 

and seek FDA approval of drug 

products. The drug approval process is 

critical to ensure patient access to 

pharmaceuticals whose quality, safety, 

and effectiveness have been established. 

The conditions that section 503B of 

the FD&C Act places on compounding 

by outsourcing facilities, including 

conditions on compounding using bulk 

drug substances, help to mitigate the 

risks associated with compounded drug 

products and protect patient health. 

Among these is the condition that 

directs FDA to place a bulk drug 

substance on the list of bulk drug 

substances that outsourcing facilities 

can use in compounding (503B Bulks 

List) only if there is a clinical need for 

outsourcing facilities to compound drug 

products using the bulk drug substance. 

B. Statutory and Regulatory Background 

Section 503B of the FD&C Act 

describes the conditions that must be 

satisfied for drug products compounded 

by an outsourcing facility to be exempt 

from section 505 (21 U.S.C. 355) 

(concerning the approval of drugs under 

new drug applications (NDAs) or 

abbreviated new drug applications 

(ANDAs)); section 502(f)(1) (21 U.S.C. 

352(f)(1)) (concerning the labeling of 

drugs with adequate directions for use); 

and section 582 (21 U.S.C. 360eee–1) 

(concerning drug supply chain security 

requirements).3

Drug products compounded under the 

conditions in section 503B are not 

exempt from CGMP requirements in 

section 501(a)(2)(B) of the FD&C Act (21 

U.S.C. 351(a)(2)(B)).4 Outsourcing 

facilities are also subject to FDA 


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5Section 503B(b)(4) and (5) of the FD&C Act. 

6Section 503B(d)(4)(C) of the FD&C Act. 

7Section 503B(a)(2)(A) of the FD&C Act. 

8 21 CFR 207.3. 

9Section 503B(a)(2) of the FD&C Act and 21 CFR 

207.1. 

10 Inactive ingredients are not subject to section 

503B(a)(2) of the FD&C Act and will not be 

included in the 503B Bulks List because they are 

not included within the definition of a bulk drug 

substance. Pursuant to section 503B(a)(3), inactive 

ingredients used in compounding must comply 

with the standards of an applicable United States 

Pharmacopeia or National Formulary monograph, if 

a monograph exists. 

11This is consistent with procedure set forth in 

section 503B(a)(2)(A)(i). Although the statute only 

directs FDA to issue a Federal Register notice and 

seek public comment when it proposes to include 

bulk drug substances on the 503B Bulks List, we 

intend to seek comment when the Agency has 

evaluated a nominated substance and proposes 

either to include or not to include the substance on 

the list. 

12Section 503B does not require FDA to consult 

the PCAC before developing a 503B Bulks List. 

13On June 10, 2016, FDA announced the 

availability of a guidance for industry that provides 

additional information regarding FDA’s policies for 

bulk drug substances nominated for the 503B Bulks 

List pending our review of nominated substances 

under the ‘‘clinical need’’ standard entitled 

‘‘Interim Policy on Compounding Using Bulk Drug 

Substances Under Section 503B of the Federal 

Food, Drug, and Cosmetic Act’’ (81 FR 37502); 

available at https://www.fda.gov/downloads/Drugs/ 

GuidanceComplianceRegulatoryInformation/ 

Guidances/UCM469122.pdf. 

14On March 26, 2018, FDA announced the 

availability of a draft guidance entitled ‘‘Evaluation 

of Bulk Drug Substances Nominated for Use in 

Compounding Under Section 503B of the Federal 

Food, Drug, and Cosmetic Act’’ (503B Bulks 

Evaluation Guidance) (83 FR 12952); available at 

https://www.fda.gov/downloads/Drugs/Guidance

ComplianceRegulatoryInformation/Guidances/ 

UCM602276.pdf. The draft guidance proposes 

policies for developing the 503B Bulks List, 

including the interpretation of the phrase ‘‘bulk 

drug substances for which there is a clinical need,’’ 

as it is used in section 503B. The Agency is 

considering comments it received on this draft 

guidance and is working to finalize the guidance. 

inspections according to a risk-based 

schedule, specific adverse event 

reporting requirements, and other 

conditions that help to mitigate the risks 

of the drug products they compound.5

Outsourcing facilities may or may not 

obtain prescriptions for identified 

individual patients and can, therefore, 

distribute compounded drugs to 

healthcare practitioners for ‘‘office 

stock,’’ to hold in their offices in 

advance of patient need.6

One of the conditions that must be 

met for a drug product compounded by 

an outsourcing facility to qualify for 

exemptions under section 503B is that 

the outsourcing facility may not 

compound a drug using a bulk drug 

substance unless (a) the bulk drug 

substance appears on a list established 

by the Secretary identifying bulk drug 

substances for which there is a clinical 

need (the 503B Bulks List); or (b) the 

drug compounded from such bulk drug 

substances appears on the drug shortage 

list in effect under section 506E of the 

FD&C Act (FDA’s drug shortage list) (21 

U.S.C. 356e) at the time of 

compounding, distribution, and 

dispensing.7

For purposes of section 503B, bulk 

drug substance means an active 

pharmaceutical ingredient as defined in 

21 CFR 207.1(b).8 Active pharmaceutical 

ingredient means any substance that is 

intended for incorporation into a 

finished drug product and is intended to 

furnish pharmacological activity or 

other direct effect in the diagnosis, cure, 

mitigation, treatment, or prevention of 

disease, or to affect the structure or any 

function of the body, but the term does 

not include intermediates used in the 

synthesis of the substance.9 10

II. Methodology for Developing the 

503B Bulks List 

A. Process for Developing the List 

In the Federal Register of December 4, 

2013 (78 FR 72838), FDA requested 

nominations for specific bulk drug 

substances for the Agency to consider 

for inclusion on the 503B Bulks List. In 

response to that request, interested 

groups and individuals nominated a 

wide variety of substances. However, 

many of those nominations were not for 

substances used in compounding as 

active pharmaceutical ingredients or did 

not include sufficient information to 

allow FDA to evaluate the nominated 

substance. To improve the efficiency of 

the process for the development of the 

list of bulk drug substances, FDA 

reopened the nomination process in the 

Federal Register of July 2, 2014 (79 FR 

37750), and provided more detailed 

information on what it needs to evaluate 

nominations for the list. On October 27, 

2015 (80 FR 65770), the Agency opened 

a new docket, FDA–2015–N–3469, to 

provide an opportunity for interested 

persons to submit new nominations of 

bulk drug substances or to re-nominate 

substances with sufficient information. 

As FDA evaluates bulk drug 

substances, it intends to publish notices 

for public comment in the Federal 

Register that describe its proposed 

position on each substance along with 

the rationale for that position.11 After 

considering any comments on FDA’s 

proposals regarding whether to include 

nominated substances on the 503B 

Bulks List, FDA intends to consider 

whether input from the Pharmacy 

Compounding Advisory Committee 

(PCAC) on the nominations would be 

helpful to the Agency in making its 

determination, and if so, it will seek 

PCAC input.12 Depending on its review 

of the docket comments and other 

relevant information before the Agency, 

FDA may finalize its proposed 

determination without change, or it may 

finalize a modification to its proposal to 

reflect new evidence or analysis 

regarding clinical need. FDA will then 

publish in the Federal Register a list 

identifying the bulk drug substances for 

which it has determined there is a 

clinical need and FDA’s rationale in 

making that final determination. FDA 

will also publish in the Federal Register 

a list of those substances it considered 

but found that there is no clinical need 

to use in compounding and FDA’s 

rationale in making this decision. 

FDA intends to maintain a current list 

of all bulk drug substances it has 

evaluated on its website, with separate 

lists for bulk drug substances it has 

placed on the 503B Bulks List and those 

it has decided not to place on the 503B 

Bulks List. FDA will only place a bulk 

drug substance on the 503B Bulks List 

where it has determined there is a 

clinical need for outsourcing facilities to 

compound drug products using the bulk 

drug substance. If a clinical need to 

compound drug products using the bulk 

drug substance has not been 

demonstrated, based on the information 

submitted by the nominator and any 

other information considered by the 

Agency, FDA will not place a bulk drug 

substance on the 503B Bulks List. 

FDA intends to evaluate the bulk drug 

substances nominated for the 503B 

Bulks List on a rolling basis. FDA will 

evaluate and publish in the Federal 

Register its proposed and final 

determinations in groups of bulk drug 

substances until all nominated 

substances that were sufficiently 

supported have been evaluated and 

either placed on the 503B Bulks List or 

identified as bulk drug substances that 

were considered but determined not to 

be appropriate for inclusion on the 503B 

Bulks List.13

B. Analysis of Substances Nominated 

for the List 

As noted above, the 503B Bulks List 

will include bulk drug substances for 

which there is a clinical need. The 

Agency is beginning its evaluation of 

some of the bulk drug substances that 

were nominated for inclusion on the 

503B Bulks List, proceeding case by 

case, under the standard provided by 

the statute.14 In applying this standard 

to develop the proposals in this notice, 

FDA is interpreting the phrase ‘‘bulk 

drug substances for which there is a 

clinical need’’ to mean that the 503B 

Bulks List may include a bulk drug 

substance if: (1) There is a clinical need 

for an outsourcing facility to compound 


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15According to FDA’s proposal in its 503B Bulks 

Evaluation Guidance, the additional analysis would 

consist of the application of four additional factors. 

We did not answer ‘‘yes’’ to both of the threshold 

questions for bumetanide, nicardipine 

hydrochloride, or vasopressin, and we did not 

consider these four additional factors in our 

proposal not to include bumetanide, nicardipine 

hydrochloride, or vasopressin on the 503B Bulks 

List. 

16See Docket No. FDA–2015–N–3469, document 

no. FDA–2015–N–3469–0013. 

17See, e.g., labeling available as of the date of this 

notice at https://www.accessdata.fda.gov/spl/data/ 

f983b4df-996d-4558-adf7-ee4be1b3a03a/f983b4df996d-4558-adf7-ee4be1b3a03a.xml. 

18Bumetanide is also approved as an oral tablet. 

See, e.g., ANDA 074225. 

19For example, the nomination does not take the 

position or provide support for a position that a 

drug product prepared by starting with the 

approved drug would be unsuitable for 

administration. 

20The nomination also states that bumetanide 

should be added to the 503B Bulks List because 

compounding from the bulk drug substance could 

allow outsourcing facilities to address issues such 

as drug shortages, product accessibility, and/or 

affordability. As noted above, section 503B contains 

a separate provision for compounding from bulk 

drug substances to address a drug shortage, and we 

do not interpret the other price- and supply-related 

reasons advanced by the nomination to fall within 

the statutory definition of ‘‘clinical need.’’ 

21See Docket No. FDA–2015–N–3469, document 

no. FDA–2015–N–3469–0002. 

the drug product and (2) the drug 

product must be compounded using the 

bulk drug substance. FDA is not 

interpreting supply issues, such as 

backorders, to be within the meaning of 

‘‘clinical need’’ for compounding with a 

bulk drug substance. Section 503B 

separately provides for compounding 

from bulk drug substances under the 

exemptions from the FD&C Act 

discussed above if the drug product 

compounded from the bulk drug 

substance is on the FDA drug shortage 

list at the time of compounding, 

distribution, and dispensing. 

Additionally, we are not considering 

cost of the compounded drug product as 

compared with an FDA-approved drug 

product to be within the meaning of 

‘‘clinical need.’’ 

The bulk drug substances that we are 

addressing in this notice are 

components of FDA-approved drug 

products, and we therefore began our 

evaluation by asking the following 

questions: 

(a) Is there a basis to conclude, for 

each FDA-approved product that 

includes the nominated bulk drug 

substance, that (i) an attribute of the 

FDA-approved drug product makes it 

medically unsuitable to treat certain 

patients for a condition that FDA has 

identified for evaluation, and (ii) the 

drug product proposed to be 

compounded is intended to address that 

attribute? 

(b) Is there a basis to conclude that the 

drug product proposed to be 

compounded must be produced from a 

bulk drug substance rather than from an 

FDA-approved drug product? 

The reason for question (a) is that 

unless an attribute of the FDA-approved 

drug is medically unsuitable for certain 

patients, and a drug product 

compounded using a bulk drug 

substance that is a component of the 

approved drug is intended to address 

that attribute, there is no clinical need 

to compound a drug product using that 

bulk drug substance. Rather, such 

compounding would unnecessarily 

expose patients to the risks associated 

with drug products that do not meet the 

standards applicable to FDA-approved 

drug products for safety, effectiveness, 

quality, and labeling and would 

undermine the drug approval process. 

The reason for question (b) is that to 

place a bulk drug substance on the 503B 

Bulks List, FDA must determine that 

there is a clinical need for outsourcing 

facilities to compound a drug product 

using the bulk drug substance rather 

than starting with an FDA-approved 

drug product. 

If the answer to both of these 

questions is ‘‘yes,’’ there may be clinical 

need for outsourcing facilities to 

compound using the bulk drug 

substance, and we would analyze the 

question further.15 If the answer to 

either of these questions is ‘‘no,’’ we 

generally would not include the bulk 

drug substance on the 503B Bulks List, 

because there would not be a basis to 

conclude that there may be a clinical 

need to compound drug products using 

the bulk drug substance instead of 

administering or starting with an 

approved drug product. 

III. Substances Proposed for the 503B 

Bulks List 

The three bulk drug substances that 

have been evaluated to date and that 

FDA is proposing not to place on the 

list, and the reasons for those proposals, 

are as follows: 

1. Bumetanide 

Bumetanide has been nominated for 

inclusion on the 503B Bulks List to 

compound a drug product that manages 

edema associated with congestive heart 

failure, cirrhosis, and renal disease.16

The proposed route of administration is 

intravenous infusion, the proposed 

dosage form is injection, and the 

proposed strength is 0.1 milligrams per 

milliliter (mg/mL). The nominated bulk 

drug substance is a component of FDAapproved drug products (e.g., ANDAs 

074332 and 079196). FDA-approved 

bumetanide is available as a 0.25 mg/mL 

injection that may be administered 

parenterally (intravenously or 

intramuscularly) to patients in whom 

gastrointestinal absorption may be 

impaired or in whom oral 

administration is not practical.17 18

Because bumetanide is a component 

of an FDA-approved drug product, we 

considered whether there is a basis to 

conclude that the drug product 

proposed to be compounded must be 

compounded using a bulk drug 

substance. The nomination does not 

provide a basis to conclude that a bulk 

drug substance must be used to prepare 

a drug product containing bumetanide 

at concentrations below the 

concentration of the FDA-approved drug 

product (0.25 mg/mL). The nomination 

states that it may not be safer to prepare 

a drug product at such concentrations 

by starting with the approved drug; 

however, the nomination also 

recognizes that doing so would only 

require a dilution. It does not take the 

position or provide support for a 

position that a bulk drug substance must 

be used to prepare these concentrations 

of bumetanide.19 20

Accordingly, FDA finds no basis to 

conclude that the drug products 

proposed to be compounded at a lower 

concentration than FDA-approved 

bumetanide must be compounded using 

a bulk drug substance rather than the 

approved drug product. We also find no 

basis to conclude that there is a clinical 

need for an outsourcing facility to 

compound a drug product using the 

bulk drug substance bumetanide and, 

therefore, we propose to not include 

bumetanide on the 503B Bulks List. 

Because we are proposing not to 

include bumetanide on the 503B Bulks 

List for this reason, we do not consider 

question (a) in the analysis described 

above—whether an attribute of the FDAapproved drug product makes it 

medically unsuitable to treat certain 

patients and whether the drug product 

proposed to be compounded is intended 

to address that attribute. 

2. Nicardipine Hydrochloride 

Nicardipine hydrochloride has been 

nominated for inclusion on the 503B 

Bulks List.21 The proposed route of 

administration is intravenous, the 

proposed dosage form is injection, and 

the proposed strength is 0.1–2.5 mg/mL. 

This nominated bulk drug substance is 

a component of FDA-approved drug 

products (e.g., NDAs 022276 and 

019734). FDA has approved nicardipine 

hydrochloride drug products as 0.1 mg/ 

mL and 0.2 mg/mL ready-to-use 

solutions for intravenous administration 


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22See, e.g., labeling available as of the date of this 

notice at https://www.accessdata.fda.gov/spl/data/ 

32756b4e-a977-47ac-9620-0c1ed74d7606/ 

32756b4e-a977-47ac-9620-0c1ed74d7606.xml 

(ready-to-administer) and https://

www.accessdata.fda.gov/spl/data/5444784f-fefe4352-afd1-b4c487165f3a/5444784f-fefe-4352-afd1- 

b4c487165f3a.xml (for dilution). 

23Nicardipine hydrochloride is also approved as 

an oral capsule. See, e.g., ANDA 074642. 

24For example, the nomination does not take the 

position or provide support for a position that a 

drug product prepared by starting with the 

approved drug product would be unsuitable for 

patient administration. 

25The nomination also states that nicardipine 

hydrochloride should be added to the 503B Bulks 

List because compounding from bulk could help 

outsourcing facilities to address drug shortages and 

inconsistencies in supply of generic injections. As 

noted in section II., section 503B of the FD&C Act 

already provides for compounding from bulk drug 

substances to address a drug shortage, and we do 

not interpret the other price- and supply-related 

reasons stated in the nomination to constitute 

clinical need. 

26See Docket No. FDA–2015–N–3469, documents 

nos. FDA–2015–N–3469–0012 and –0023. 

27The labeling as of the date of this notice is 

available at https://www.accessdata.fda.gov/spl/ 

data/4166e423-659e-4fe4-8a3c-2394434d00dd/ 

4166e423-659e-4fe4-8a3c-2394434d00dd.xml. 

28For example, the nomination does not take the 

position or provide support for a position that a 

drug product prepared by starting with the 

approved drug product would be unsuitable for 

patient administration. 

29One of the nominations also states that 

vasopressin should be added to the 503B Bulks List 

because compounding from the bulk drug substance 

could allow outsourcing facilities to address issues 

such as drug shortages, product accessibility, and/ 

or affordability. As noted above, section 503B 

contains a separate provision for compounding 

from bulk drug substances to address a drug 

shortage, and we do not interpret the other priceand supply-related reasons advanced by the 

nomination to fall within the statutory definition of 

‘‘clinical need.’’ 

and as a 2.5 mg/mL single-dose vial that 

must be diluted prior to infusion.22 23

Because nicardipine hydrochloride is 

a component of an FDA-approved drug 

product, we considered whether there is 

a basis to conclude that the drug 

product proposed to be compounded 

must be compounded using a bulk drug 

substance. The nomination does not 

provide a basis to conclude that a bulk 

drug substance must be used to prepare 

drug products containing nicardipine 

hydrochloride at concentrations at or 

below the concentrations of the FDAapproved products (0.1, 0.2, and 2.5 mg/ 

mL) and for the same route of 

administration (intravenous) as that 

described in the approved drug product 

labeling. Initially, we note that two 

nicardipine drug products are approved 

in ready-to-administer form (e.g., no 

further dilutions needed) at 

concentrations within the range 

described in the nominations. The 

nomination does not present a reason to 

compound a drug product from a bulk 

drug substance at these concentrations. 

With respect to other concentrations, 

the nomination asserts, without support, 

that it would be safer to use a bulk drug 

substance than to start with the 

approved drug product. However, the 

nomination does not take the position or 

provide support for the position that a 

bulk drug substance must be used to 

prepare these concentrations of 

nicardipine hydrochloride.24 In fact, the 

approved labeling of another 

nicardipine hydrochloride drug product 

directs the drug product to be diluted to 

a concentration within that range.25

Accordingly, FDA finds no basis to 

conclude that the drug products 

proposed to be compounded at a 

concentration at or lower than FDAapproved nicardipine hydrochloride 

must be compounded using a bulk drug 

substance rather than the approved drug 

product. We also find no basis to 

conclude that there is clinical need for 

an outsourcing facility to compound 

using the bulk drug substance 

nicardipine hydrochloride and, 

therefore, we propose to not include 

nicardipine hydrochloride on the 503B 

Bulks List. Because we are proposing 

not to include nicardipine 

hydrochloride on the 503B Bulks List 

for this reason, we do not consider 

question (a) in the analysis described 

above—whether an attribute of the FDAapproved drug product makes it 

medically unsuitable to treat certain 

patients and whether the drug product 

proposed to be compounded is intended 

to address that attribute. 

3. Vasopressin 

Vasopressin was nominated for 

inclusion on the 503B Bulks List to 

compound a drug product that treats 

septic shock, post-cardiotomy shock, 

diabetes insipidus, and hypotension.26

The proposed route of administration is 

intravenous; the proposed dosage form 

is injection. The nominators proposed a 

range of specific concentrations (0.1, 

0.2, 0.4, and 1 units/mL (U/mL)), and 

also concentrations above that of the 

approved drug product without 

identifying any specific concentration. 

This nominated bulk drug substance is 

the active ingredient of the FDAapproved drug VASOSTRICT (NDA 

204485). VASOSTRICT is approved as a 

20 U/mL intravenous infusion that, per 

its labeling, should be diluted with 

normal saline or 5 percent dextrose in 

water to either 0.1 U/mL or 1 U/mL for 

intravenous administration.27

Because vasopressin is a component 

of an FDA-approved drug product, we 

considered the nominations under 

questions (a) and (b) of the analysis 

described previously. 

One of the nominations proposes 

vasopressin for the 503B Bulks List so 

that it can be used to compound a drug 

product whose concentration of 

vasopressin is higher than undiluted 

VASOSTRICT. The nomination does not 

identify an attribute of VASOSTRICT 

that makes it medically unsuitable for 

patients and that such highconcentration products are intended to 

address. The nomination does not 

identify any data or information as to 

the need for a higher concentration than 

the approved product, nor does the 

nomination identify specific higher 

concentrations it proposes to 

compound. In addition, the information 

provided in the nomination does not 

identify patients for whom a 

concentration at or below 20 U/mL is 

medically unsuitable and who would 

therefore require a higher concentration, 

and FDA is not aware of patients who 

would need concentrations above 20 U/ 

mL. 

Both nominations propose 

vasopressin for the 503B Bulks List so 

that it can be used to compound drug 

products whose concentrations of 

vasopressin are lower than undiluted 

VASOSTRICT. The nominations do not 

provide a basis to conclude that a bulk 

drug substance must be used to prepare 

a drug product that contains vasopressin 

at concentrations below the 

concentration of VASOSTRICT (20 

U/mL) and uses the same diluents 

(dextrose and sodium chloride) and the 

same route of administration 

(intravenous) as that described in the 

approved product labeling. The 

nominations do not take the position or 

provide support for the position that a 

bulk drug substance rather than the 

FDA-approved drug product must be 

used to prepare these lower 

concentrations of vasopressin.28 In fact, 

VASOSTRICT’s approved labeling 

directs VASOSTRICT to be diluted 

using the diluents described in the 

nominations to concentrations within 

which the drug products proposed to be 

compounded fall.29

Accordingly, FDA finds no basis to 

conclude that an attribute of 

VASOSTRICT makes it medically 

unsuitable to treat patients such that 

patients would need a higher 

concentration higher than that of 

VASOSTRICT. FDA also finds no basis 

to conclude that the drug products 

proposed to be compounded at a lower 

concentration than VASOSTRICT must 

be compounded using a bulk drug 

substance rather than the approved 

drug. Further, we find no basis to 

conclude that there is a clinical need for 

an outsourcing facility to compound 


daltland on DSKBBV9HB2PROD with NOTICES
43882 Federal Register / Vol. 83, No. 167 / Tuesday, August 28, 2018 / Notices 

using the bulk drug substance 

vasopressin and, therefore, we propose 

to not include vasopressin on the 503B 

Bulks List. 

Dated: August 23, 2018. 

Leslie Kux, 

Associate Commissioner for Policy. 

[FR Doc. 2018–18614 Filed 8–27–18; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Office of the Secretary 

Notice of Interest Rate on Overdue 

Debts 

Section 30.18 of the Department of 

Health and Human Services’ claims 

collection regulations (45 CFR part 30) 

provides that the Secretary shall charge 

an annual rate of interest, which is 

determined and fixed by the Secretary 

of the Treasury after considering private 

consumer rates of interest on the date 

that the Department of Health and 

Human Services becomes entitled to 

recovery. The rate cannot be lower than 

the Department of Treasury’s current 

value of funds rate or the applicable rate 

determined from the ‘‘Schedule of 

Certified Interest Rates with Range of 

Maturities’’ unless the Secretary waives 

interest in whole or part, or a different 

rate is prescribed by statute, contract, or 

repayment agreement. The Secretary of 

the Treasury may revise this rate 

quarterly. The Department of Health and 

Human Services publishes this rate in 

the Federal Register. 

The current rate of 101⁄4%, as fixed by 

the Secretary of the Treasury, is certified 

for the quarter ended June 30, 2018. 

This rate is based on the Interest Rates 

for Specific Legislation, ‘‘National 

Health Services Corps Scholarship 

Program (42 U.S.C. 254o(b)(1)(A))’’ and 

‘‘National Research Service Award 

Program (42 U.S.C. 288(c)(4)(B)).’’ This 

interest rate will be applied to overdue 

debt until the Department of Health and 

Human Services publishes a revision. 

Dated: August 23, 2018. 

David C. Horn, 

Director, Office of Financial Policy and 

Reporting. 

[FR Doc. 2018–18648 Filed 8–27–18; 8:45 am] 

BILLING CODE 4150–04–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

[Document Identifier: OS–0990—New] 

Agency Information Collection 

Request. 60-Day Public Comment 

Request 

AGENCY: Office of the Secretary, HHS. 

ACTION: Notice. 

SUMMARY: In compliance with the 

requirement of the Paperwork 

Reduction Act of 1995, the Office of the 

Secretary (OS), Department of Health 

and Human Services, is publishing the 

following summary of a proposed 

collection for public comment. 

DATES: Comments on the ICR must be 

received on or before October 29, 2018. 

ADDRESSES: Submit your comments to 

Sherrette.Funn@hhs.gov or by calling 

(202) 795–7714. 

FOR FURTHER INFORMATION CONTACT: 

When submitting comments or 

requesting information, please include 

the document identifier 0990–New— 

60D and project title for reference., to 

Sherrette.funn@hhs.gov, or call 202– 

795–7714, Sherrette Funn, the Reports 

Clearance Officer. 

SUPPLEMENTARY INFORMATION: Interested 

persons are invited to send comments 

regarding this burden estimate or any 

other aspect of this collection of 

information, including any of the 

following subjects: (1) The necessity and 

utility of the proposed information 

collection for the proper performance of 

the agency’s functions; (2) the accuracy 

of the estimated burden; (3) ways to 

enhance the quality, utility, and clarity 

of the information to be collected; and 

(4) the use of automated collection 

techniques or other forms of information 

technology to minimize the information 

collection burden. 

Title of the Collection: Cross-Site 

Evaluation on the Women’s Health 

College Sexual Assault Policy and 

Prevention Initiative. 

Type of Collection: New. 

OMB No. 0990–XXXX: Office of 

Women’s Health within OS. 

Abstract: The Office of Women’s 

Health is seeking an approval by OMB 

on a new information collection, CrossSite Evaluation on the Women’s Health 

College Sexual Assault. The purpose of 

this data collection is to gather 

qualitative data across the nine grantee 

organizations and partners via 

interviews to gain a full understanding 

of grantee and partner perceived success 

over the course of the three-year project; 

grantee and partner experiences with 

the initiative; barriers and facilitators to 

project implementation; sustainability 

of grantee efforts; and anecdotal or other 

evidence of reductions in campus 

sexual violence. Interviews conducted 

with individuals representing the 

grantee organizations and campus 

partners, and will occur once per 

respondent in the spring of 2019. 

The CDC estimates that 23 million 

women have experienced completed or 

attempted rape in their lifetimes. 

(National Intimate Partner and Sexual 

Violence Survey, https://www.cdc.gov/ 

mmwr/preview/mmwrhtml/ 

ss6308a1.htm). A September 2015 

Association of American Universities 

(AAU) survey of 150,000 students across 

27 colleges and universities indicated 

that 23% of female undergraduate 

students reported experiencing sexual 

assault since enrolling in college (AAU 

Campus Climate Survey on Sexual 

Assault and Sexual Misconduct, https:// 

www.aau.edu/sites/default/files/ 

%40%20Files/Climate%20Survey/ 

Executive%20Summary%2012-14- 

15.pdf). 

The College Sexual Assault Policy, 

and Prevention Initiative of the 

Department of Health and Human 

Services, Office of Women’s Health, has 

three main goals: (1) Disseminate sexual 

assault policy and prevention 

information to organizations in a 

position to influence and implement 

policies and practices at post-secondary 

schools; (2) provide technical assistance 

to post-secondary schools to establish 

policies and practices that prevent 

sexual assault; and (3) assess the success 

of policy establishment and sustained 

prevention strategies enacted by 

partnering organizations and postsecondary schools. 


daltland on DSKBBV9HB2PROD with NOTICES