Bulk Drug Substances That May Be Used To Compound Drug Products in Accordance With Section 503B of the Federal Food, Drug, and Cosmetic Act, Concerning Outsourcing Facilities; Revised Request for Nominations, 37750-37754 [2014-15373]
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Column A—What information is requested?
Column B—Put data specific to the nominated substance
Is the ingredient listed in any of the three sections of the Orange
Book?
Were any monographs for the ingredient found in the USP or NF
monographs?
What is the chemical name of the substance? ........................................
What is the common name of the substance? ........................................
Does the substance have a UNII Code? .................................................
What is the chemical grade of the substance? ........................................
What is the strength, quality, stability, and purity of the ingredient? .......
How is the ingredient supplied? ...............................................................
Is the substance recognized in foreign pharmacopeias or registered in
other countries?
Has information been submitted about the substance to the USP for
consideration of monograph development?
What dosage form(s) will be compounded using the bulk drug substance?
What strength(s) will be compounded from the nominated substance?
Confirm whether the ingredient is a component of an FDA-approved
product.
Confirm whether the ingredient is the subject of a USP or NF monograph.
Chemical name.
Common name.
UNII code.
Provide the chemical grade.
Provide the strength, quality, stability, and purity information.
Describe how the ingredient is supplied (e.g., powder, liquid).
List the foreign pharmacopeias or other countries in which it is registered.
Put yes, no, or unknown. If yes, state the status of the monograph, if
known.
State the dosage form(s).
What are the anticipated route(s) of administration of the compounded
drug product(s)?
Are there safety and efficacy data on compounded drugs using the
nominated substance?
Has the bulk drug substance been used previously to compound drug
product(s)?
What is the proposed use for the drug product(s) to be compounded
with the nominated substance?
What is the reason for use of a compounded drug product rather than
an FDA-approved product?
Is there any other relevant information?
Interested persons may submit either
electronic nominations to https://
www.regulations.gov or written
nominations to the Division of Dockets
Management (see ADDRESSES). It is only
necessary to send one set of
nominations. Identify nominations with
the docket number found in the brackets
in the heading of this document.
Received nominations may be seen in
the Division of Dockets Management
between 9 a.m. and 4 p.m., Monday
through Friday, and will be posted to
the docket at https://
www.regulations.gov.
Dated: June 25, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
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List the strength(s) of the drug product(s) that will be compounded from
the nominated substance, or a range of strengths, if known.
List the route(s) of administration of the compounded drug product(s).
Provide a bibliography of safety and efficacy data for the drug compounded using the nominated substance, if available, including any
relevant peer-reviewed medical literature.
Describe past uses of the bulk drug substance in compounding.
Provide information on the proposed use of the compounded drug
product.
Provide a rationale for the use of a compounded drug product.
Provide any other information you would like FDA to consider in evaluating the nomination.
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA–2013–N–1524]
Bulk Drug Substances That May Be
Used To Compound Drug Products in
Accordance With Section 503B of the
Federal Food, Drug, and Cosmetic Act,
Concerning Outsourcing Facilities;
Revised Request for Nominations
AGENCY:
Food and Drug Administration,
HHS.
Notice; revised request for
nominations.
ACTION:
The Food and Drug
Administration (FDA or Agency) is
preparing to develop a list of bulk drug
substances (active ingredients) that may
be used to compound drug products in
accordance with section 503B of the
Federal Food, Drug, and Cosmetic Act
(the FD&C Act) concerning outsourcing
facilities. In response to a notice
published in the Federal Register of
December 4, 2013, interested groups and
individuals previously nominated a
wide variety of substances for this list.
However, many of those nominations
were not for bulk drug substances used
in compounding as active ingredients,
and none included sufficient
information to justify inclusion of the
SUMMARY:
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nominated substances on the list. To
improve the efficiency of the process for
developing the list of bulk drug
substances that may be used to
compound drug products under section
503B of the FD&C Act, FDA is providing
more detailed information on what it
needs to evaluate a nomination. Because
the deadline for nominations has
passed, FDA is reopening the
nomination process so that interested
persons can submit nominations of bulk
drug substances and provide adequate
support to justify placing the substances
on the list. Bulk drug substances that
were previously nominated will not be
further considered unless they are
renominated and adequately supported.
Substances that are not adequately
supported will not be placed on the list.
Submit written or electronic
nominations for the bulk drug
substances list by September 30, 2014.
DATES:
You may submit
nominations, identified by Docket No.
FDA–2013–N–1524, by any of the
following methods.
ADDRESSES:
Electronic Submissions
Submit electronic nominations in the
following way:
• Federal eRulemaking Portal: https://
www.regulations.gov. Follow the
instructions for submitting comments.
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Written Submissions
Submit written nominations in the
following ways:
• Mail/Hand delivery/Courier (for
paper submissions): Division of Dockets
Management (HFA–305), Food and Drug
Administration, 5630 Fishers Lane, Rm.
1061, Rockville, MD 20852.
Instructions: All submissions received
must include the Agency name and
Docket No. FDA–2013–N–1524 for this
request for nominations. All
nominations received may be posted
without change to https://
www.regulations.gov, including any
personal information provided. For
additional information on submitting
nominations, see the ‘‘Request for
Nominations’’ heading of the
SUPPLEMENTARY INFORMATION section of
this document.
Docket: For access to the docket to
read background documents or
nominations 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 Division of Dockets
Management, 5630 Fishers Lane, Rm.
1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT:
Emily Helms Williams, Center for Drug
Evaluation and Research, Food and
Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 6280,
Silver Spring, MD 20993–0002, 301–
796–3381.
SUPPLEMENTARY INFORMATION:
I. Background
Under the Drug Quality and Security
Act (Pub. L. 113–54), which added
section 503B to the Federal Food, Drug,
and Cosmetic Act (FD&C Act) (21 U.S.C.
353b), outsourcing facilities 1 may
qualify for certain exemptions from the
FD&C Act if the conditions set forth in
the statute are satisfied. Those
conditions include that an outsourcing
facility does not compound drug
products using a bulk drug substance
unless 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
list), or the drug product compounded
from such bulk drug substance appears
on the drug shortage list in effect under
section 506E of the FD&C Act (21 U.S.C.
356e) (FDA drug shortage list) at the
time of compounding, distribution, and
dispensing, and each of the following
conditions are met: (1) If an applicable
1 ‘‘Outsourcing facilities’’ are facilities that meet
certain conditions described in section 503B of the
FD&C Act, including registering with FDA as an
outsourcing facility.
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monograph exists under the United
States Pharmacopeia, the National
Formulary, or another compendium or
pharmacopeia recognized by the
Secretary for purposes of this paragraph,
the bulk drug substance complies with
the monograph; (2) the bulk drug
substance is manufactured by an
establishment that is registered under
section 510 of the FD&C Act (21 U.S.C.
360); and (3) the bulk drug substance is
accompanied by a valid certificate of
analysis (see section 503B(a)(2) of the
FD&C Act).
Section 503B refers to the definition
of ‘‘bulk drug substance’’ in FDA
regulations at § 207.3(a)(4) (21 CFR
207.3(a)(4)). See section 503B(a)(2) of
the FD&C Act. As defined in
§ 207.3(a)(4), a ‘‘bulk drug substance’’ is
any substance that is represented for use
in a drug and that, when used in the
manufacturing, processing, or packaging
of a drug, becomes an active ingredient
or a finished dosage form of the drug,
but the term does not include
intermediates used in the synthesis of
such substances.
An ‘‘active ingredient’’ is any
component that 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 of man or other animals. The
term includes those components that
may undergo chemical change in the
manufacture of the drug product and be
present in the drug product in a
modified form intended to furnish the
specified activity or effect. See 21 CFR
210.3(b)(7).
Any component other than an active
ingredient is an ‘‘inactive ingredient.’’
See 21 CFR 210.3(b)(8). Inactive
ingredients used in compounded drug
products, which commonly include
flavorings, dyes, diluents, or other
excipients, need not appear on the
Secretary’s list of bulk drug substances
to be eligible for use in compounding
drug products and will not be included
on the list.
In a notice dated November 27, 2013,
published 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 placement on the 503B list.
In response to that request, 753
comments were submitted to the docket,
most of which nominated substances for
inclusion on the bulk drug substances
list. Some comments nominated several
hundred substances, and approximately
10 comments nominated thousands of
substances, including en bloc
nominations of substances listed in the
United States Pharmacopeia (USP) or
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National Formulary, the British
Pharmacopeia, the European
Pharmacopeia, the Japanese
Pharmacopeia, the Food Chemicals
Codex, the Homeopathic Pharmacopeia
of the United States, and the USP
Dietary Supplements Compendium.
Several submissions referenced a
spreadsheet entitled ‘‘OTC Active
Ingredients,’’ available on FDA’s Web
site at https://www.fda.gov/downloads/
AboutFDA/CentersOffices/CDER/
UCM135688.pdf. Those submissions
nominated all of the ingredients on the
spreadsheet, which numbered over
1,700 entries.2
However, many of the nominated
substances are typically inactive
ingredients or foods. Some commonly
used inactive ingredients are
occasionally used as the active
ingredient in a drug product. See 55 FR
46914 at 46916, November 7, 1990
(noting that 21 CFR 310.545 only affects
the use of the listed ingredients as active
ingredients for the specific indications
and that some of the ingredients listed
in the rule, such as sorbitol, sugars, and
eucalyptol, have valid uses as inactive
ingredients). Ingredients commonly
used as inactive ingredients in
compounded drug products, such as
flavorings, dyes, diluents, or other
excipients, need not appear on the
Secretary’s list of bulk drug substances
to be eligible for use as an inactive
ingredient in compounded drug
products, should not be nominated, and
will not be included on the list. All
nominations must demonstrate how the
ingredient is used as an active
ingredient in a particular compounded
drug product.
Further, the nominations did not
include sufficient information for the
Agency to evaluate the clinical need for
drug products compounded using the
bulk drug substance. As stated
previously, section 503B requires FDA
to create a list ‘‘identifying bulk drug
substances for which there is a clinical
need . . . .’’ Section 503B(a)(2)(A)(i) of
the FD&C Act. Although this language is
ambiguous, the Agency has interpreted
it to mean that a clinical need to
compound with a bulk drug substance
exists where there is a clinical need for
a specific drug product to be
compounded with the nominated bulk
drug substance. The Agency believes
that this interpretation is consistent
with both the language and purpose of
2 The total number of unique ingredients on the
spreadsheet available on FDA’s Web site and the
nominations that mirrored that document is lower
than this total because the same substances were
listed separately for different indications, according
to how they are listed in the over-the-counter (OTC)
monographs and regulations.
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the statute. Therefore, to qualify for
placement on the 503B list, it is
necessary to identify the compounded
drug product for which there is a
clinical need and to demonstrate that
the nominated bulk drug substance is
required to compound that drug
product.
The nominators of the en bloc
submissions provided no justification
for listing any of the specific substances
on the list. To the extent information
about the clinical need for the use of a
bulk drug substance in compounded
drug products was provided at all in
individual nominations, many of the
comments to the docket included a
statement about the need for the use of
bulk drug substances in compounding
generally rather than information about
the specific clinical need for drug
products compounded using a
particular bulk drug substance. For
example, many nominations included
the following standardized language as
the explanation of clinical need for
compounding with the bulk drug
substance: ‘‘Prescribed dosage forms
and strengths not available
commercially. Manufacturer backorders.
Possible patient sensitivities to
manufactured product dyes, fillers,
preservatives and other excipients.’’
Such statements do not provide
sufficient information for FDA to
determine that there is a clinical need
to compound a particular drug product
from the nominated bulk drug
substance. Because the information
submitted with previous nominations
was insufficient, FDA is unable to
determine whether those substances
should be included on the list.
To improve the efficiency of the
process for the development of the list
of bulk drug substances that may be
used to compound drug products under
section 503B of the FD&C Act, and
because the deadline for submitting
nominations has passed, FDA is
reopening the nomination process so
that interested persons have the
opportunity to submit nominations of
bulk drug substances and provide
adequate support for placing them on
the list. FDA will be able to evaluate
only those bulk drug substances
submitted in response to this notice that
are supported with adequate data and
information, as described in section II.
Bulk drug substances that were
previously nominated will not be
further considered unless they are
renominated and adequately supported.
Substances that are not adequately
supported will not be placed on the list.
FDA expects the submissions for each
bulk drug substance to provide the
information described in section II. For
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example, nominations must include
sufficient information to demonstrate
that a particular ingredient meets the
definition of ‘‘bulk drug substance,’’ as
defined in § 207.3(a)(4). See section
503B(a)(2) of the FD&C Act. The
identification of an ingredient as an
‘‘active ingredient’’ in a regulation, or
on a spreadsheet such as the one listing
‘‘OTC Active Ingredients,’’ is not
sufficient to demonstrate that a
substance is a bulk drug substance for
purposes of the 503B List. En bloc
nominations of substances listed in
compendia, pharmacopeia, or similar
reference materials cannot be placed on
the list unless the Agency receives
adequate information for each bulk drug
substance to justify its placement on the
list. FDA will only be able to consider
bulk drug substances that are supported
with the information requested in
section II.
In section II, FDA identifies the type
of information needed to support a
nomination to the 503B list.
II. Request for Nominations
A. Active Ingredients
Interested groups and individuals
may nominate specific bulk substances
for inclusion on the list. Nominations
will only be evaluated if they are for
specific active ingredients that meet the
definition of a bulk drug substance in
§ 207.3(a)(4). Nominated substances that
do not meet this definition will not be
included on the list.
To fully evaluate a bulk drug
substance, FDA needs the following
information about both the bulk drug
substance being nominated and the drug
product(s) that will be compounded
using such substance:
1. Confirmation That the Nominated
Substance Is a Bulk Drug Substance
A statement that the nominated
substance is an active ingredient that
meets the definition of ‘‘bulk drug
substance’’ in § 207.3(a)(4), and an
explanation of why the substance is
considered an active ingredient when it
is used in compounded drug products,
citing to specific sources that describe
the active properties of the substance.
2. General Background on the Bulk Drug
Substance
• Ingredient name;
• chemical name;
• common name(s); and
• identifying codes, as available, from
FDA’s Unique Ingredient Identifiers
(UNII) used in the FDA/USP Substance
Registration System, available at https://
fdasis.nlm.nih.gov/srs/. Because
substance names can vary, this code,
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where available, will be used by the
Agency to confirm the exact substance
nominated and to identify multiple
nominations of the same substance so
the information can be reviewed
together.
• Chemical grade of the ingredient;
• description of the strength, quality,
stability, and purity of the ingredient;
• information about how the
ingredient is supplied (e.g., powder,
liquid); and
• information about recognition of the
substance in foreign pharmacopeias and
the status of its registration(s) in other
countries, including whether
information has been submitted to USP
for consideration of monograph
development.
B. Clinical Need To Compound
For FDA to be able to meaningfully
evaluate a substance, the information
provided regarding the clinical need for
compounding with a bulk drug
substance must be specific to the
particular substance nominated and
drug product to be compounded. A
‘‘boilerplate’’ or general explanation of
clinical need for compounding with
bulk drug substances will not enable
FDA to conduct an adequate review.
Prescribers of the compounded drug
products who may be in the best
position to explain why there is a
clinical need for a compounded drug
product may provide data in support of
a nomination. The following
information about clinical need is
necessary to provide adequate support
for nominations to the 503B list:
• A statement describing the medical
condition(s) that the drug product to be
compounded with the nominated bulk
drug substances is intended to treat (i.e.,
what patient need is met by the drug
product compounded with the bulk
drug substance);
• a list of FDA-approved drug
products, if any, that address the same
medical condition;
• if there are FDA-approved drug
products that address the same medical
condition, an explanation of why a
compounded drug product is necessary
(i.e., why the approved drug product is
not suitable for a particular patient
population);
• if the approved drug product is not
suitable for a particular patient
population, an estimate of the size of the
population that would need a
compounded drug product (e.g., for a
drug product compounded from bulk
because of patient allergies or other
intolerances to excipients in FDAapproved drug products, FDA expects
the supporting information to include a
good faith estimate of the patient
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population with the specific medical
condition that suffers from the allergy or
intolerance, with citations to the
literature regarding the incidence of the
condition or a statement that a search
was conducted and no references were
found); 3
• a bibliography of safety and efficacy
data for the drug compounded using the
nominated substance,4 if available,
including any relevant peer-reviewed
medical literature; and
• if there is an FDA-approved drug
product that includes the bulk drug
substance nominated, an explanation of
why the drug product proposed to be
compounded must be compounded
from bulk rather than with the FDAapproved drug product.
General or boilerplate statements
regarding the need to compound from
the bulk drug substance or the benefits
of compounding generally will not be
considered sufficient. Note that the
Agency does not consider supply issues,
such as backorders, that do not rise to
the level of a drug shortage listed on
FDA’s drug shortage Web site as
evidence of a clinical need for
compounding with a bulk drug
substance, and section 503B of the
FD&C Act already allows compounding
from bulk drug substances if the
compounded drug product is on the
FDA drug shortage list. Similarly,
considerations of cost and convenience
will not be considered indicators of
clinical need.
C. Information on the Drug Product
That Will Be Compounded With the
Bulk Drug Substance
• Information about the dosage
form(s) into which the bulk drug
substance will be compounded;
• information about the strength(s) of
the compounded drug product(s);
• information about the anticipated
route(s) of administration of the
compounded drug product(s); and
• information about the previous
use(s) of the compounded drug
product(s).
D. Nomination Process
Because the deadline for submitting
nominations has passed, FDA is
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reopening the nomination process so
that interested persons can submit
nominations of bulk drug substances
and have the opportunity to provide
adequate support for placing them on
the list. Bulk drug substances that were
previously nominated need to be
renominated. Nominators are
encouraged to submit as much of the
information identified in this document
as possible. Unless adequate supporting
data is received for a bulk drug
substance, FDA will be unable to
consider it further for inclusion on the
list.
Individuals and organizations will be
able to comment on nominated
substances after the nomination period
has closed or petition FDA to make
additional list amendments after the list
is published, in accordance with 21 CFR
10.30.
For efficient consolidation and review
of nominations, nominators are
encouraged to submit their nominations
in an editable Excel file. Specifically,
nominators are encouraged to format
their nominations as follows:
Column A—What information is requested?
Column B—put data specific to the nominated substance
What is the name of the nominated ingredient? ......................................
Is the ingredient an active ingredient that meets the definition of ‘‘bulk
drug substance’’ in § 207.3(a)(4)?
Provide the ingredient name.
Provide an explanation for why it is considered an active ingredient
when it is used in specific compounded drug products, and provide
citations to specific sources that describe its active properties.
Chemical name.
Common name.
UNII code.
Provide the chemical grade.
Provide the strength, quality, stability, and purity information.
Describe how the ingredient is supplied (e.g., powder, liquid).
List the foreign pharmacopeias or other countries in which it is registered.
Put yes, no, or unknown. If yes, state the status of the monograph, if
known.
Describe the medical condition(s) that the drug product compounded
with the bulk drug substances is intended to treat.
List the other approved treatments.
What is the chemical name of the substance? ........................................
What is the common name of the substance? ........................................
Does the substance have a UNII Code? .................................................
What is the chemical grade of the substance? ........................................
What is the strength, quality, stability, and purity of the ingredient? .......
How is the ingredient supplied? ...............................................................
Is the substance recognized in foreign pharmacopeias or registered in
other countries?
Has information been submitted about the substance to the USP for
consideration of monograph development?
What medical condition(s) is the drug product compounded with the
bulk drug substances intended to treat?
Are there other drug products approved by FDA to treat the same medical condition?
If there are FDA-approved drug products that address the same medical condition, why is there a clinical need for a compounded drug
product?
Are there safety and efficacy data on compounded drugs using the
nominated substance?
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If there is an FDA-approved drug product that includes the bulk drug
substance nominated, is it necessary to compound a drug product
from the bulk drug substance rather than from the FDA-approved
drug product?
What dosage form(s) will be compounded using the bulk drug substance?
What strength(s) will be compounded from the nominated substance?
What are the anticipated route(s) of administration of the compounded
drug product(s)?
3 For example, if there is a need to compound a
drug product from bulk drug substances due to
patient sensitivity to a preservative or other
excipient in the approved drug product, the
supporting data is expected to set forth the number
of patients for whom the drug product is prescribed
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Provide a justification for clinical need, including an estimate of the size
of the population that would need the compounded drug.
Provide a bibliography of safety and efficacy data for the drug compounded using the nominated substance, if available, including any
relevant peer-reviewed medical literature.
Provide an explanation of why it is necessary to compound from the
bulk drug substance.
State the dosage form(s).
List the strength(s) of the drug product(s) that will be compounded from
the nominated substance, or a range of strengths, if known.
List the route(s) of administration of the compounded drug product(s).
that are allergic or sensitive to that particular
excipient.
4 FDA recognizes that the available safety and
efficacy data supporting consideration of a bulk
drug substance for inclusion on the list may not be
of the same type, amount, or quality as is required
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to support a new drug application. Note that data
regarding safety and efficacy, while relevant, is not
indicative of a clinical need for a particular bulk
drug substance, and additional information
regarding the clinical need must be provided.
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Column A—What information is requested?
Column B—put data specific to the nominated substance
Has the bulk drug substance been used previously to compound drug
product(s)?
Is there any other relevant information? ..................................................
Interested persons may submit either
electronic nominations to https://
www.regulations.gov or written
nominations to the Division of Dockets
Management (see ADDRESSES). It is only
necessary to send one set of
nominations. Identify nominations with
the docket number found in the brackets
in the heading of this document.
Received nominations may be seen in
the Division of Dockets Management
between 9 a.m. and 4 p.m., Monday
through Friday, and will be posted to
the docket at https://
www.regulations.gov.
Dated: June 25, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
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DEPARTMENT OF HEALTH AND
HUMAN SERVICES
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Statement of Organization, Functions
and Delegations of Authority
This notice amends Part R of the
Statement of Organization, Functions
and Delegations of Authority of the
Department of Health and Human
Services (HHS), Health Resources and
Services Administration (HRSA) (60 FR
56605, as amended November 6, 1995;
67 FR 46519, as amended June 11, 2008;
73 FR 33099, as amended September 30,
2009, 78 FR 50227, as last amended
January 24, 2013, 78 FR 7436). This
Order of Succession supersedes the
Order of Succession for the
Administrator, HRSA, published at 78
FR 7436, February 1, 2013.
This notice deletes the Bureau of
Health Professions; the Bureau of
Clinician Recruitment and Services; and
Regional Division Directors from the
order of succession, and adds the
Bureau of Health Workforce and
Regional Administrators to HRSA’s
hierarchy affecting the Order of
Succession. This notice reflects the new
Order of Succession for HRSA.
Section R–30, Order of Succession
During the absence or disability of the
Administrator, or in the event of a
vacancy in the office, the officials
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Provide any other information you would like FDA to consider in evaluating the nomination.
designated below shall act as
Administrator in the order in which
they are listed:
1. Deputy Administrator;
2. Chief Operating Officer;
3. Associate Administrator, Bureau of
Primary Health Care;
4. Associate Administrator, Bureau of
Health Workforce;
5. Associate Administrator, HIV/AIDS
Bureau;
6. Associate Administrator, Maternal
and Child Health Bureau;
7. Associate Administrator,
Healthcare Systems Bureau;
8. Associate Administrator, Office of
Regional Operations; and
9. HRSA Regional Administrators in
the order in which they have received
their permanent appointment as such.
Exceptions
Health Resources and Services
Administration
VerDate Mar<15>2010
Describe previous uses of the bulk drug substance in compounding.
(a) No official listed in this section
who is serving in acting or temporary
capacity shall, by virtue of so serving,
act as Administrator pursuant to this
section.
(b) Notwithstanding the provisions of
this section, during a planned period of
absence, the Administrator retains the
discretion to specify a different order of
succession.
Section R–40, Delegations of Authority
All delegations of authority and redelegations of authority made to HRSA
officials that were in effect immediately
prior to this action, and that are
consistent with this action, shall
continue in effect pending further redelegation, pending further redelegation, provided they are consistent
with this action.
This document is effective upon date
of signature.
Dated: June 25, 2014.
Mary K. Wakefield,
Administrator.
[FR Doc. 2014–15498 Filed 7–1–14; 8:45 am]
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Frm 00044
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DEPARTMENT OF HEALTH AND
HUMAN SERVICES
National Institutes of Health
Submission for OMB Review; 30-Day
Comment Request; Population
Assessment of Tobacco and Health
(PATH) Study
Under the provisions of
Section 3507(a)(1)(D) of the Paperwork
Reduction Act of 1995, the National
Institute on Drug Abuse (NIDA), the
National Institutes of Health (NIH), has
submitted to the Office of Management
and Budget (OMB) a request for review
and approval of the information
collection listed below. This proposed
information collection was previously
published in the Federal Register on
February 6, 2014, pages 7206–7207, and
allowed 60-days for public comment.
One public comment was received. The
purpose of this notice is to allow an
additional 30 days for public comment.
The National Institutes of Health may
not conduct or sponsor, and the
respondent is not required to respond
to, an information collection that has
been extended, revised, or implemented
on or after October 1, 1995, unless it
displays a currently valid OMB control
number.
Direct Comments to OMB: Written
comments and/or suggestions regarding
the item(s) contained in this notice,
especially regarding the estimated
public burden and associated response
time, should be directed to the: Office
of Management and Budget, Office of
Regulatory Affairs, OIRA_Submission@
omb.eop.gov or by fax to 202–395–6974,
Attention: NIH Desk Officer.
Comment Due Date: Comments
regarding this information collection are
best assured of having their full effect if
received within 30-days of the date of
this publication.
FOR FURTHER INFORMATION CONTACT: To
obtain a copy of the data collection
plans and instruments, submit
comments in writing, or request more
information on the proposed project
contact: Kevin P. Conway, Ph.D.,
Deputy Director, Division of
Epidemiology, Services, and Prevention
Research, National Institute on Drug
Abuse, 6001 Executive Boulevard.,
Room 5185; or call non-toll-free number
(301)-443–8755; or Email your request,
SUMMARY:
E:\FR\FM\02JYN1.SGM
02JYN1
]]>Agencies
[Federal Register Volume 79, Number 127 (Wednesday, July 2, 2014)]
[Notices]
[Pages 37750-37754]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2014-15373]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2013-N-1524]
Bulk Drug Substances That May Be Used To Compound Drug Products
in Accordance With Section 503B of the Federal Food, Drug, and Cosmetic
Act, Concerning Outsourcing Facilities; Revised Request for Nominations
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice; revised request for nominations.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA or Agency) is preparing
to develop a list of bulk drug substances (active ingredients) that may
be used to compound drug products in accordance with section 503B of
the Federal Food, Drug, and Cosmetic Act (the FD&C Act) concerning
outsourcing facilities. In response to a notice published in the
Federal Register of December 4, 2013, interested groups and individuals
previously nominated a wide variety of substances for this list.
However, many of those nominations were not for bulk drug substances
used in compounding as active ingredients, and none included sufficient
information to justify inclusion of the nominated substances on the
list. To improve the efficiency of the process for developing the list
of bulk drug substances that may be used to compound drug products
under section 503B of the FD&C Act, FDA is providing more detailed
information on what it needs to evaluate a nomination. Because the
deadline for nominations has passed, FDA is reopening the nomination
process so that interested persons can submit nominations of bulk drug
substances and provide adequate support to justify placing the
substances on the list. Bulk drug substances that were previously
nominated will not be further considered unless they are renominated
and adequately supported. Substances that are not adequately supported
will not be placed on the list.
DATES: Submit written or electronic nominations for the bulk drug
substances list by September 30, 2014.
ADDRESSES: You may submit nominations, identified by Docket No. FDA-
2013-N-1524, by any of the following methods.
Electronic Submissions
Submit electronic nominations in the following way:
Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments.
[[Page 37751]]
Written Submissions
Submit written nominations in the following ways:
Mail/Hand delivery/Courier (for paper submissions):
Division of Dockets Management (HFA-305), Food and Drug Administration,
5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
Instructions: All submissions received must include the Agency name
and Docket No. FDA-2013-N-1524 for this request for nominations. All
nominations received may be posted without change to https://www.regulations.gov, including any personal information provided. For
additional information on submitting nominations, see the ``Request for
Nominations'' heading of the SUPPLEMENTARY INFORMATION section of this
document.
Docket: For access to the docket to read background documents or
nominations 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 Division of
Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Emily Helms Williams, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 6280, Silver Spring, MD 20993-0002, 301-
796-3381.
SUPPLEMENTARY INFORMATION:
I. Background
Under the Drug Quality and Security Act (Pub. L. 113-54), which
added section 503B to the Federal Food, Drug, and Cosmetic Act (FD&C
Act) (21 U.S.C. 353b), outsourcing facilities \1\ may qualify for
certain exemptions from the FD&C Act if the conditions set forth in the
statute are satisfied. Those conditions include that an outsourcing
facility does not compound drug products using a bulk drug substance
unless 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 list), or the drug product compounded from such
bulk drug substance appears on the drug shortage list in effect under
section 506E of the FD&C Act (21 U.S.C. 356e) (FDA drug shortage list)
at the time of compounding, distribution, and dispensing, and each of
the following conditions are met: (1) If an applicable monograph exists
under the United States Pharmacopeia, the National Formulary, or
another compendium or pharmacopeia recognized by the Secretary for
purposes of this paragraph, the bulk drug substance complies with the
monograph; (2) the bulk drug substance is manufactured by an
establishment that is registered under section 510 of the FD&C Act (21
U.S.C. 360); and (3) the bulk drug substance is accompanied by a valid
certificate of analysis (see section 503B(a)(2) of the FD&C Act).
---------------------------------------------------------------------------
\1\ ``Outsourcing facilities'' are facilities that meet certain
conditions described in section 503B of the FD&C Act, including
registering with FDA as an outsourcing facility.
---------------------------------------------------------------------------
Section 503B refers to the definition of ``bulk drug substance'' in
FDA regulations at Sec. 207.3(a)(4) (21 CFR 207.3(a)(4)). See section
503B(a)(2) of the FD&C Act. As defined in Sec. 207.3(a)(4), a ``bulk
drug substance'' is any substance that is represented for use in a drug
and that, when used in the manufacturing, processing, or packaging of a
drug, becomes an active ingredient or a finished dosage form of the
drug, but the term does not include intermediates used in the synthesis
of such substances.
An ``active ingredient'' is any component that 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 of man or other
animals. The term includes those components that may undergo chemical
change in the manufacture of the drug product and be present in the
drug product in a modified form intended to furnish the specified
activity or effect. See 21 CFR 210.3(b)(7).
Any component other than an active ingredient is an ``inactive
ingredient.'' See 21 CFR 210.3(b)(8). Inactive ingredients used in
compounded drug products, which commonly include flavorings, dyes,
diluents, or other excipients, need not appear on the Secretary's list
of bulk drug substances to be eligible for use in compounding drug
products and will not be included on the list.
In a notice dated November 27, 2013, published 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
placement on the 503B list. In response to that request, 753 comments
were submitted to the docket, most of which nominated substances for
inclusion on the bulk drug substances list. Some comments nominated
several hundred substances, and approximately 10 comments nominated
thousands of substances, including en bloc nominations of substances
listed in the United States Pharmacopeia (USP) or National Formulary,
the British Pharmacopeia, the European Pharmacopeia, the Japanese
Pharmacopeia, the Food Chemicals Codex, the Homeopathic Pharmacopeia of
the United States, and the USP Dietary Supplements Compendium. Several
submissions referenced a spreadsheet entitled ``OTC Active
Ingredients,'' available on FDA's Web site at https://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM135688.pdf. Those submissions
nominated all of the ingredients on the spreadsheet, which numbered
over 1,700 entries.\2\
---------------------------------------------------------------------------
\2\ The total number of unique ingredients on the spreadsheet
available on FDA's Web site and the nominations that mirrored that
document is lower than this total because the same substances were
listed separately for different indications, according to how they
are listed in the over-the-counter (OTC) monographs and regulations.
---------------------------------------------------------------------------
However, many of the nominated substances are typically inactive
ingredients or foods. Some commonly used inactive ingredients are
occasionally used as the active ingredient in a drug product. See 55 FR
46914 at 46916, November 7, 1990 (noting that 21 CFR 310.545 only
affects the use of the listed ingredients as active ingredients for the
specific indications and that some of the ingredients listed in the
rule, such as sorbitol, sugars, and eucalyptol, have valid uses as
inactive ingredients). Ingredients commonly used as inactive
ingredients in compounded drug products, such as flavorings, dyes,
diluents, or other excipients, need not appear on the Secretary's list
of bulk drug substances to be eligible for use as an inactive
ingredient in compounded drug products, should not be nominated, and
will not be included on the list. All nominations must demonstrate how
the ingredient is used as an active ingredient in a particular
compounded drug product.
Further, the nominations did not include sufficient information for
the Agency to evaluate the clinical need for drug products compounded
using the bulk drug substance. As stated previously, section 503B
requires FDA to create a list ``identifying bulk drug substances for
which there is a clinical need . . . .'' Section 503B(a)(2)(A)(i) of
the FD&C Act. Although this language is ambiguous, the Agency has
interpreted it to mean that a clinical need to compound with a bulk
drug substance exists where there is a clinical need for a specific
drug product to be compounded with the nominated bulk drug substance.
The Agency believes that this interpretation is consistent with both
the language and purpose of
[[Page 37752]]
the statute. Therefore, to qualify for placement on the 503B list, it
is necessary to identify the compounded drug product for which there is
a clinical need and to demonstrate that the nominated bulk drug
substance is required to compound that drug product.
The nominators of the en bloc submissions provided no justification
for listing any of the specific substances on the list. To the extent
information about the clinical need for the use of a bulk drug
substance in compounded drug products was provided at all in individual
nominations, many of the comments to the docket included a statement
about the need for the use of bulk drug substances in compounding
generally rather than information about the specific clinical need for
drug products compounded using a particular bulk drug substance. For
example, many nominations included the following standardized language
as the explanation of clinical need for compounding with the bulk drug
substance: ``Prescribed dosage forms and strengths not available
commercially. Manufacturer backorders. Possible patient sensitivities
to manufactured product dyes, fillers, preservatives and other
excipients.'' Such statements do not provide sufficient information for
FDA to determine that there is a clinical need to compound a particular
drug product from the nominated bulk drug substance. Because the
information submitted with previous nominations was insufficient, FDA
is unable to determine whether those substances should be included on
the list.
To improve the efficiency of the process for the development of the
list of bulk drug substances that may be used to compound drug products
under section 503B of the FD&C Act, and because the deadline for
submitting nominations has passed, FDA is reopening the nomination
process so that interested persons have the opportunity to submit
nominations of bulk drug substances and provide adequate support for
placing them on the list. FDA will be able to evaluate only those bulk
drug substances submitted in response to this notice that are supported
with adequate data and information, as described in section II.
Bulk drug substances that were previously nominated will not be
further considered unless they are renominated and adequately
supported. Substances that are not adequately supported will not be
placed on the list. FDA expects the submissions for each bulk drug
substance to provide the information described in section II. For
example, nominations must include sufficient information to demonstrate
that a particular ingredient meets the definition of ``bulk drug
substance,'' as defined in Sec. 207.3(a)(4). See section 503B(a)(2) of
the FD&C Act. The identification of an ingredient as an ``active
ingredient'' in a regulation, or on a spreadsheet such as the one
listing ``OTC Active Ingredients,'' is not sufficient to demonstrate
that a substance is a bulk drug substance for purposes of the 503B
List. En bloc nominations of substances listed in compendia,
pharmacopeia, or similar reference materials cannot be placed on the
list unless the Agency receives adequate information for each bulk drug
substance to justify its placement on the list. FDA will only be able
to consider bulk drug substances that are supported with the
information requested in section II.
In section II, FDA identifies the type of information needed to
support a nomination to the 503B list.
II. Request for Nominations
A. Active Ingredients
Interested groups and individuals may nominate specific bulk
substances for inclusion on the list. Nominations will only be
evaluated if they are for specific active ingredients that meet the
definition of a bulk drug substance in Sec. 207.3(a)(4). Nominated
substances that do not meet this definition will not be included on the
list.
To fully evaluate a bulk drug substance, FDA needs the following
information about both the bulk drug substance being nominated and the
drug product(s) that will be compounded using such substance:
1. Confirmation That the Nominated Substance Is a Bulk Drug Substance
A statement that the nominated substance is an active ingredient
that meets the definition of ``bulk drug substance'' in Sec.
207.3(a)(4), and an explanation of why the substance is considered an
active ingredient when it is used in compounded drug products, citing
to specific sources that describe the active properties of the
substance.
2. General Background on the Bulk Drug Substance
Ingredient name;
chemical name;
common name(s); and
identifying codes, as available, from FDA's Unique
Ingredient Identifiers (UNII) used in the FDA/USP Substance
Registration System, available at https://fdasis.nlm.nih.gov/srs/.
Because substance names can vary, this code, where available, will be
used by the Agency to confirm the exact substance nominated and to
identify multiple nominations of the same substance so the information
can be reviewed together.
Chemical grade of the ingredient;
description of the strength, quality, stability, and
purity of the ingredient;
information about how the ingredient is supplied (e.g.,
powder, liquid); and
information about recognition of the substance in foreign
pharmacopeias and the status of its registration(s) in other countries,
including whether information has been submitted to USP for
consideration of monograph development.
B. Clinical Need To Compound
For FDA to be able to meaningfully evaluate a substance, the
information provided regarding the clinical need for compounding with a
bulk drug substance must be specific to the particular substance
nominated and drug product to be compounded. A ``boilerplate'' or
general explanation of clinical need for compounding with bulk drug
substances will not enable FDA to conduct an adequate review.
Prescribers of the compounded drug products who may be in the best
position to explain why there is a clinical need for a compounded drug
product may provide data in support of a nomination. The following
information about clinical need is necessary to provide adequate
support for nominations to the 503B list:
A statement describing the medical condition(s) that the
drug product to be compounded with the nominated bulk drug substances
is intended to treat (i.e., what patient need is met by the drug
product compounded with the bulk drug substance);
a list of FDA-approved drug products, if any, that address
the same medical condition;
if there are FDA-approved drug products that address the
same medical condition, an explanation of why a compounded drug product
is necessary (i.e., why the approved drug product is not suitable for a
particular patient population);
if the approved drug product is not suitable for a
particular patient population, an estimate of the size of the
population that would need a compounded drug product (e.g., for a drug
product compounded from bulk because of patient allergies or other
intolerances to excipients in FDA-approved drug products, FDA expects
the supporting information to include a good faith estimate of the
patient
[[Page 37753]]
population with the specific medical condition that suffers from the
allergy or intolerance, with citations to the literature regarding the
incidence of the condition or a statement that a search was conducted
and no references were found); \3\
---------------------------------------------------------------------------
\3\ For example, if there is a need to compound a drug product
from bulk drug substances due to patient sensitivity to a
preservative or other excipient in the approved drug product, the
supporting data is expected to set forth the number of patients for
whom the drug product is prescribed that are allergic or sensitive
to that particular excipient.
---------------------------------------------------------------------------
a bibliography of safety and efficacy data for the drug
compounded using the nominated substance,\4\ if available, including
any relevant peer-reviewed medical literature; and
---------------------------------------------------------------------------
\4\ FDA recognizes that the available safety and efficacy data
supporting consideration of a bulk drug substance for inclusion on
the list may not be of the same type, amount, or quality as is
required to support a new drug application. Note that data regarding
safety and efficacy, while relevant, is not indicative of a clinical
need for a particular bulk drug substance, and additional
information regarding the clinical need must be provided.
---------------------------------------------------------------------------
if there is an FDA-approved drug product that includes the
bulk drug substance nominated, an explanation of why the drug product
proposed to be compounded must be compounded from bulk rather than with
the FDA-approved drug product.
General or boilerplate statements regarding the need to compound
from the bulk drug substance or the benefits of compounding generally
will not be considered sufficient. Note that the Agency does not
consider supply issues, such as backorders, that do not rise to the
level of a drug shortage listed on FDA's drug shortage Web site as
evidence of a clinical need for compounding with a bulk drug substance,
and section 503B of the FD&C Act already allows compounding from bulk
drug substances if the compounded drug product is on the FDA drug
shortage list. Similarly, considerations of cost and convenience will
not be considered indicators of clinical need.
C. Information on the Drug Product That Will Be Compounded With the
Bulk Drug Substance
Information about the dosage form(s) into which the bulk
drug substance will be compounded;
information about the strength(s) of the compounded drug
product(s);
information about the anticipated route(s) of
administration of the compounded drug product(s); and
information about the previous use(s) of the compounded
drug product(s).
D. Nomination Process
Because the deadline for submitting nominations has passed, FDA is
reopening the nomination process so that interested persons can submit
nominations of bulk drug substances and have the opportunity to provide
adequate support for placing them on the list. Bulk drug substances
that were previously nominated need to be renominated. Nominators are
encouraged to submit as much of the information identified in this
document as possible. Unless adequate supporting data is received for a
bulk drug substance, FDA will be unable to consider it further for
inclusion on the list.
Individuals and organizations will be able to comment on nominated
substances after the nomination period has closed or petition FDA to
make additional list amendments after the list is published, in
accordance with 21 CFR 10.30.
For efficient consolidation and review of nominations, nominators
are encouraged to submit their nominations in an editable Excel file.
Specifically, nominators are encouraged to format their nominations as
follows:
------------------------------------------------------------------------
Column A--What information is Column B--put data specific to
requested? the nominated substance
------------------------------------------------------------------------
What is the name of the nominated Provide the ingredient name.
ingredient?.
Is the ingredient an active ingredient Provide an explanation for why
that meets the definition of ``bulk it is considered an active
drug substance'' in Sec. ingredient when it is used in
207.3(a)(4)? specific compounded drug
products, and provide
citations to specific sources
that describe its active
properties.
What is the chemical name of the Chemical name.
substance?.
What is the common name of the Common name.
substance?.
Does the substance have a UNII Code?... UNII code.
What is the chemical grade of the Provide the chemical grade.
substance?.
What is the strength, quality, Provide the strength, quality,
stability, and purity of the stability, and purity
ingredient?. information.
How is the ingredient supplied?........ Describe how the ingredient is
supplied (e.g., powder,
liquid).
Is the substance recognized in foreign List the foreign pharmacopeias
pharmacopeias or registered in other or other countries in which it
countries? is registered.
Has information been submitted about Put yes, no, or unknown. If
the substance to the USP for yes, state the status of the
consideration of monograph monograph, if known.
development?
What medical condition(s) is the drug Describe the medical
product compounded with the bulk drug condition(s) that the drug
substances intended to treat? product compounded with the
bulk drug substances is
intended to treat.
Are there other drug products approved List the other approved
by FDA to treat the same medical treatments.
condition?
If there are FDA-approved drug products Provide a justification for
that address the same medical clinical need, including an
condition, why is there a clinical estimate of the size of the
need for a compounded drug product? population that would need the
compounded drug.
Are there safety and efficacy data on Provide a bibliography of
compounded drugs using the nominated safety and efficacy data for
substance? the drug compounded using the
nominated substance, if
available, including any
relevant peer-reviewed medical
literature.
If there is an FDA-approved drug Provide an explanation of why
product that includes the bulk drug it is necessary to compound
substance nominated, is it necessary from the bulk drug substance.
to compound a drug product from the
bulk drug substance rather than from
the FDA-approved drug product?
What dosage form(s) will be compounded State the dosage form(s).
using the bulk drug substance?
What strength(s) will be compounded List the strength(s) of the
from the nominated substance? drug product(s) that will be
compounded from the nominated
substance, or a range of
strengths, if known.
What are the anticipated route(s) of List the route(s) of
administration of the compounded drug administration of the
product(s)? compounded drug product(s).
[[Page 37754]]
Has the bulk drug substance been used Describe previous uses of the
previously to compound drug bulk drug substance in
product(s)? compounding.
Is there any other relevant Provide any other information
information?. you would like FDA to consider
in evaluating the nomination.
------------------------------------------------------------------------
Interested persons may submit either electronic nominations to
https://www.regulations.gov or written nominations to the Division of
Dockets Management (see ADDRESSES). It is only necessary to send one
set of nominations. Identify nominations with the docket number found
in the brackets in the heading of this document. Received nominations
may be seen in the Division of Dockets Management between 9 a.m. and 4
p.m., Monday through Friday, and will be posted to the docket at https://www.regulations.gov.
Dated: June 25, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-15373 Filed 7-1-14; 8:45 am]
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