[Federal Register Volume 86, Number 171 (Wednesday, September 8, 2021)]
[Notices]
[Pages 50363-50365]
[FR Doc No: 2021-19335]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2019-N-5464]

Center for Drug Evaluation and Research Office of New Drugs Novel
Excipient Review Pilot Program

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration's (FDA) Center for Drug
Evaluation and Research (CDER) is announcing a Novel Excipient Review
Pilot Program (Pilot Program). The Pilot Program is voluntary and
intended to allow excipient manufacturers to obtain FDA review of
certain novel excipients prior to their use in drug formulations. The
Pilot Program seeks to foster development of excipients that may be
useful in scenarios in which excipient manufacturers and drug
developers have cited difficulty in using existing excipients.

DATES: FDA is seeking initial proposals for the voluntary Novel
Excipient Review Pilot Program through December 7, 2021.

FOR FURTHER INFORMATION CONTACT: Felecia Wilson, Center for Drug
Evaluation and Research, Food and Drug Administration<EMAIL_ADDRESS>301-796-9590.

SUPPLEMENTARY INFORMATION:

I. Background

    Excipient manufacturers and drug developers have cited product
development challenges related to the use of certain excipients (also
known as inactive ingredients), including issues related to formulation
and stability. Novel excipients might be able to address some of these
issues and provide additional public health benefits, such as enhanced
drug bioavailability, more comfortable drug administration, new abuse-
deterrent opioid formulations, new routes of drug delivery, and
facilitation of new technologies. However, drug developers report that
they have been hesitant to use novel excipients in drug development
programs due to the uncertainty surrounding their acceptability.
    To address these issues, FDA issued a request for information in
the Federal Register on December 5, 2019 (84 FR 66669), seeking comment
on a potential pilot program for FDA review of novel excipients. FDA
received several comments to the public docket on these issues. After
considering these comments, CDER has decided to establish this Pilot
Program.

A. Scope

    For purposes of the Pilot Program, an excipient is any ingredient
intentionally added to a drug product (including a biological drug
product) that is not intended to exert therapeutic effects at the
intended dosage, although it may improve product delivery (see FDA
guidance for industry entitled ``Nonclinical Studies for the Safety
Evaluation of Pharmaceutical Excipients'' (Ref.1)). Examples of
excipients may include fillers, extenders, diluents, surfactants,
solvents, emulsifiers, preservatives, flavors, absorption enhancers,
modified release matrices, and coloring agents. Also, for purposes of
this Pilot Program, a novel excipient is any excipient that is not
fully supported by existing safety data with respect to the currently
proposed level of exposure, duration of exposure, or route of
administration (Ref. 1). This parallels the definition of ``new
excipients'' defined in Ref. 1.
    CDER proposes a more limited scope for this Pilot Program. The
Pilot Program will initially be available for novel excipients that (1)
have not been previously used in FDA-approved drug products, and (2) do
not have an established use in food. CDER recognizes that there may be
novel excipients not meeting this scope that may also address product
development challenges or provide public health benefits. However,
because of the limited scope of the initial phase of the Pilot Program
(described further below), CDER will not be able to consider
submissions for all kinds of novel excipients. CDER may expand the
scope of the Pilot Program in the future depending on its success and
as resources allow.
    The Pilot Program is voluntary. Existing processes for developing
excipients for use in drug and biological products continue to be
available.

B. Participation

    The Pilot Program will consist of two stages. The first stage is an
initial proposal stage for excipient manufacturers to provide a high-
level overview of their novel excipient. CDER intends to accept
approximately four initial proposals (two for the first year of the
Pilot Program, and two for the second year) but will consider accepting
more proposals as resources allow. Excipient manufacturers whose
initial proposals are accepted would then enter the second stage,
during which they would provide a full data package consisting of
toxicology and quality data. Both stages are described in further
detail below.
    As mentioned above, CDER intends to consider for the Pilot Program
novel excipients that (1) have not been previously used in FDA-approved
drug products, and (2) do not have an established use in food.

C. Procedures

1. Initial Proposal Stage
    At the initial proposal stage, excipient manufacturers will submit
brief summaries describing the novel excipient, its proposed use, and
the public health or drug development need addressed by the excipient.
The initial proposal is anticipated to include a summary of the
supportive data generated or collected so far and some indication of
the timing of any subsequent data needed for submission of the Full
Package. FDA has posted an initial proposal model content outline on
the Pilot Program web page (https://www.fda.gov/drugs/development-approval-process-drugs/novel-excipient-review-pilot-program).
    Interested excipient manufacturers should submit initial proposals
to FDA via email at<EMAIL_ADDRESS>FDA will
accept proposals for the pilot through December 7, 2021. FDA will
notify all submitters whether their proposal is accepted into the Pilot
Program.
    FDA will review the initial proposals and select approximately four
proposals (two for the first year and two for the second year) to
proceed to stage two of the program. FDA will consider the following
factors, among other considerations, in determining which proposals to
select:
     Potential public health benefit of the novel excipient
(for example, excipients that may facilitate opioid abuse-deterrent
formulations or excipients that may promote development of new
therapies for serious and life-threatening diseases).
     Likelihood of the novel excipient manufacturer's ability
to submit a complete package within the timeframe established in this
Notice.
     Overall potential of the novel excipient to meaningfully
improve pharmacokinetic characteristics that may lead to novel drug
development.
2. Procedures for Full Packages
    For novel excipients selected into the program, the developer
should submit a full package consisting of toxicology and quality data
as described below. See CDER Guidance for industry entitled
``Nonclinical Studies for the Safety Evaluation of Pharmaceutical
Excipients'' (Ref. 1).
    a. Toxicology data package. The toxicology data package should
include adequate, supportive safety information for the novel excipient
to verify that the proposed excipient is safe in the amounts and type
of product(s) in which it may be administered as well as the proposed
use (e.g., level, route, duration, patient population). Depending on
the proposed use, the toxicology data package may include the
information described below. Additional safety data may be requested if
the proposed use is not fully supported by the available data.
Reference is made to the relevant guidance for the proposed toxicology
data package below.
     Safety pharmacology: Novel excipients should be evaluated
for pharmacological activity using a battery of standard tests (see FDA
guidance for industry entitled ``S7A Safety Pharmacology Studies for
Human Pharmaceuticals'' (Ref. 2)).
     Pharmacokinetic testing (absorption, distribution,
metabolism, and excretion): To determine the extent of exposure. A
pharmacokinetic profile for an excipient that is extensively absorbed,
undergoes extensive biotransformation, or both will be useful.
     General toxicology: Chronic, 6-month repeat dose
toxicology studies in a relevant species by appropriate route with
complete clinical pathology, histopathology, and toxicokinetic analysis
are recommended. Because excipients generally have low toxicity, the
limit dose is recommended as the highest dose for testing (see FDA
guidance for industry entitled ``M3(R2) Nonclinical Safety Studies for
the Conduct of Human Clinical Trials and Marketing Authorization for
Pharmaceuticals'' (Ref. 3)).
     Genetic toxicology (see FDA guidance for industry entitled
``S2B Genotoxicity: A Standard Battery for Genotoxicity Testing of
Pharmaceuticals'' (Ref. 4)).
     Reproductive toxicology: Fertility, embryo-fetal, and pre-
and post-natal development (see International Council for Harmonization
harmonized guidance for industry entitled ``Detection of Reproductive
and Developmental Toxicity for Human Pharmaceuticals S5(R3)'' (Ref.
5)).
     Carcinogenicity: One of the following approaches may be
used to evaluate carcinogenic potential (see FDA guidance for industry
entitled ``The Need for Long-term Rodent Carcinogenicity Studies of
Pharmaceuticals'' (Ref. 6)):
    [cir] Two-year carcinogenicity bioassays in two appropriate species
by the relevant route;
    [cir] A 2-year carcinogenicity study in rat plus a transgenic mouse
model; or
    [cir] Submission of documentation providing scientific
justification that carcinogenicity data are not necessary based on the
weight of evidence approach in an assessment to address the
carcinogenic potential.
     Special studies (e.g., local tolerance, Juvenile Animal
Studies).
    b. Quality data package. The novel excipient chemistry,
manufacturing, and controls data submitted to CDER should be similar to
that provided in an investigational new drug application (IND).
    For evaluation of all novel excipients with a proposed use in
formulations for small molecule and biological drug products reviewed
by CDER/Office of New Drugs (OND), submitters should provide:
     Excipient specifications.
     A description of the source, synthetic pathway/
fermentation or extraction for non-synthetic excipients, raw materials,
in-process controls, manufacturing process description,
characterization and analytical methods, or a letter of authorization
(right of reference) for the excipient Type IV drug master file (DMF)
or other master file if a master file has been submitted for the
excipient.
     If the excipient contains a novel moiety with immunogenic
potential, an immunogenicity risk assessment that may include in vitro
data. Additional information on immunogenicity risk assessment may be
found in FDA guidance for industry entitled ``S8 Immunotoxicity Studies
for Human Pharmaceuticals'' for types of supporting in vitro studies
(Ref. 7).
     If the excipient is sourced from cells, clearance of host
cell protein (absence in final excipient) and evidence of absence of
adventitious agents such as viruses.

    In addition, for evaluation of novel excipients with a proposed use
in formulations for biological drug products reviewed by CDER/OND,
submitters should provide:
     Stability studies of the excipient under storage and
potential in-use conditions (e.g., over infusion time). Novel
excipients should be evaluated for their potential to prevent
denaturation and degradation of proteins during storage.
     For some excipients, studies should address their
potential protein-excipient interaction and impact on drug product
immunogenicity as well as their potential for masking process related
impurities.
    Full packages should be submitted through a Type V DMF or other
master file no later than 3 months after notification that FDA has
selected the proposal. For more information on submitting Type V DMFs,
see the FDA draft guidance for industry entitled ``Drug Master Files''
(Ref. 8).
    FDA will evaluate the full package and determine whether the
excipient is appropriate for the proposed use for use in clinical
trials. FDA will issue a letter to the novel excipient submitter
announcing its decision.
    For each novel excipient evaluated under the second stage of the
program, FDA will publish on the Pilot Program web page the initial
proposal and the determination letter. Information that cannot be
publicly disclosed will be redacted. This web page will also include a
content outline identifying information that should be included in an
Initial Proposal and other relevant information regarding the pilot.

3. Effect of Determination

    A determination that the excipient is appropriate for use in
clinical trials means that FDA has determined it is appropriate to use
the novel excipient in an IND within the defined use without additional
justification. However, the drug sponsor would still need to
demonstrate that the excipient is safe in the proposed formulation. The
information submitted under the full package would remain in the Type V
DMF or other master file, and the master file holder may grant
authorization to reference the information in the master file at the
holder's discretion. Moreover, we do not anticipate that a novel
excipient may be used in an abbreviated new drug application because
data and information currently required to support use of a novel
excipient may not be submitted in an abbreviated new drug application.
After it has been used in approved drug products, the novel excipient
would be added to the Inactive Ingredient Database in accordance with
Agency practice.
    If FDA determines that the excipient is not appropriate for the
proposed use, an IND sponsor would be expected to provide additional
information to demonstrate that the use of the novel excipient is
appropriate within the context of the IND.

II. Paperwork Reduction Act of 1995

    The information collection activities associated with the Pilot
Program refer to previously approved FDA collections of information.
Therefore, clearance by the Office of Management and Budget (OMB) under
the Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-3521) is not
required for this Pilot Program. The previously approved collections of
information are subject to review by OMB under the PRA. The collections
of information in 21 CFR part 314 pertaining to the submission of
abbreviated new drug applications, new drug applications, and DMFs have
been approved under OMB control number 0910-0001. The collections of
information in 21 CFR part 312 pertaining to the submission of IND
content and format; chemistry, control, and manufacturing data;
pharmacology and toxicology data; and pharmacokinetics and biological
data have been approved under OMB control number 0910-0014. The
collections of information in 21 CFR part 58 pertaining to good
laboratory practice regulations for nonclinical laboratory studies have
been approved under OMB control number 0910-0119. The collections of
information in 21 CFR part 601 pertaining to biologics license
applications have been approved under OMB control number 0910-0338.

III. References

    The following references are on display at the Dockets Management
Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm.
1061, Rockville, MD 20852,<PHONE_NUMBER>, and are available for viewing
by interested persons between 9 a.m. and 4 p.m., Monday through Friday;
they are also available electronically at https://www.regulations.gov.
FDA has verified the website addresses, as of the date this document
publishes in the Federal Register, but websites are subject to change
over time.

1. FDA, Guidance for Industry, ``Nonclinical Studies for the Safety
Evaluation of Pharmaceutical Excipients,'' May 2005 (available at
https://www.fda.gov/media/72260/download). For the most recent
version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.
2. FDA Guidance for Industry, ``S7A Safety Pharmacology Studies for
Human Pharmaceuticals,'' July 2001 (available at https://www.fda.gov/media/72033/download).
3. FDA, Guidance for Industry, ``M3(R2) Nonclinical Safety Studies
for the Conduct of Human Clinical Trials and Marketing Authorization
for Pharmaceuticals,'' January 2010 (available at https://www.fda.gov/media/71542/download).
4. FDA, Guidance for Industry, ``S2B Genotoxicity: A Standard
Battery for Genotoxicity Testing of Pharmaceuticals,'' July 1997
(available at https://www.fda.gov/media/71971/download).
5. International Council for Harmonization (ICH), Guidance for
Industry, ``Detection of Reproductive and Developmental Toxicity for
Human Pharmaceuticals S5(R3),'' February 2020 (available at https://database.ich.org/sites/default/files/S5-R3_Step4_Guideline_2020_0218_1.pdf).
6. FDA, Guidance for Industry, ``The Need for Long-term Rodent
Carcinogenicity Studies of Pharmaceuticals,'' March 1996 (available
at https://www.fda.gov/media/71921/download).
7. FDA, Guidance for Industry, ``S8 Immunotoxicity Studies for Human
Pharmaceuticals,'' April 2006 (available at https://www.fda.gov/media/72047/download).
8. FDA, Draft Guidance for Industry ``Drug Master Files,'' October
2019 (available at https://www.fda.gov/media/131861/download).

    Dated: September 1, 2021.
Lauren K. Roth,
Acting Principal Associate Commissioner for Policy.
[FR Doc. 2021-19335 Filed 9-7-21; 8:45 am]
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[Federal Register: June 2, 2006 (Volume 71, Number 106)]
[Notices]
[Page 32061]
[DOCID:fr02jn06-43]

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DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[PH06-1-000; PH06-2-000; PH06-3-000; PH06-5-000; PH06-6-000; PH06-7-
000; PH06-8-000; PH06-9-000; PH06-10-000]

Berrick Gold Corporation; DPL Inc.; AGL Resources Inc.; Hawaiian
Electronic Industries; TransCanada Corporation; Broad Street Contract
Services, Inc.; DTE Energy Company; Mitsubishi Corporation, et al.;
Kandiyohi Power Cooperative; Notice of Effectiveness of Exemptions and
Waivers

May 26, 2006.
    Take notice that in March and April 2006 the exemptions and waivers
requested in the above-captioned proceedings are deemed to have been
granted by operation of law pursuant to 18 CFR 366.4.

Magalie R. Salas,
Secretary.
[FR Doc. E6-8601 Filed 6-1-06; 8:45 am]

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[Federal Register Volume 81, Number 219 (Monday, November 14, 2016)]
[Notices]
[Page 79549]
[FR Doc No: 2016-27248]

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SECURITIES AND EXCHANGE COMMISSION

Proposed Collection; Comment Request

Upon Written Request, Copies Available From: Securities and Exchange
Commission, Office of FOIA Services, 100 F Street NE., Washington, DC
20549-2736.

Extension: Rule 201 and Rule 200(g) of Regulation SHO
    SEC File No. 270-606, OMB Control No. 3235-0670

    Notice is hereby given that pursuant to the Paperwork Reduction Act
of 1995 (44 U.S.C. 3501 et seq.) (``PRA''), the Securities and Exchange
Commission (``Commission'') is soliciting comments on the existing
collection of information provided for in Rule 201 (17 CFR 242.201) and
Rule 200(g) (17 CFR 242.200(g)) under the Securities Exchange Act of
1934 (15 U.S.C. 78a et seq.). The Commission plans to submit this
existing collection of information to the Office of Management and
Budget (``OMB'') for extension and approval.
    Rule 201 is a short sale-related circuit breaker rule that, if
triggered, imposes a restriction on the prices at which securities may
be sold short. Rule 200(g) provides that a broker-dealer may mark
certain qualifying sell orders ``short exempt.'' The information
collected under Rule 201's written policies and procedures requirement
applicable to trading centers, the written policies and procedures
requirement of the broker-dealer provision of Rule 201(c), the written
policies and procedures requirement of the riskless principal provision
of Rule 201(d)(6), and the ``short exempt'' marking requirement of Rule
200(g) enable the Commission and self-regulatory organizations
(``SROs'') to examine and monitor for compliance with the requirements
of Rule 201 and Rule 200(g).
    In addition, the information collected under Rule 201's written
policies and procedures requirement applicable to trading centers helps
to ensure that trading centers do not execute or display any
impermissibly priced short sale orders, unless an order is marked
``short exempt,'' in accordance with the rule's requirements.
Similarly, the information collected under the written policies and
procedures requirement of the broker-dealer provision of Rule 201(c)
and the riskless principal provision of Rule 201(d)(6) helps to ensure
that broker-dealers comply with the requirements of these provisions.
The information collected pursuant to the ``short exempt'' marking
requirement of Rule 200(g) also provides an indication to a trading
center of when it must execute or display a short sale order without
regard to whether the short sale order is at a price that is less than
or equal to the current national best bid.
    It is estimated that SRO and non-SRO respondents registered with
the Commission and subject to the collection of information
requirements of Rule 201 and Rule 200(g) incur an aggregate annual
burden of 2,908,309 hours to comply with the rules and an aggregate
annual external cost of $120,000.
    Written comments are invited on: (a) Whether the proposed
collection of information is necessary for the proper performance of
the functions of the Commission, including whether the information
shall have practical utility; (b) the accuracy of the Commission's
estimates of the burden of the proposed collection of information; (c)
ways to enhance the quality, utility, and clarity of the information
collected; and (d) ways to minimize the burden of the collection of
information on respondents, including through the use of automated
collection techniques or other forms of information technology.
Consideration will be given to comments and suggestions submitted in
writing within 60 days of this publication.
    An agency may not conduct or sponsor, and a person is not required
to respond to, a collection of information under the PRA unless it
displays a currently valid OMB control number.
    Please direct your written comments to: Pamela Dyson, Director/
Chief Information Officer, Securities and Exchange Commission, c/o Remi
Pavlik-Simon, 100 F Street NE., Washington, DC 20549, or send an email
to<EMAIL_ADDRESS>
    Dated: November 7, 2016.
Brent J. Fields,
Secretary.
[FR Doc. 2016-27248 Filed 11-10-16; 8:45 am]
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