Center for Drug Evaluation and Research Office of New Drugs Novel Excipient Review Pilot Program
| Citation | 86 FR 50363 |
| Record Number | 2021-19335 |
| Published date | 08 September 2021 |
| Section | Notices |
| Court | Food And Drug Administration |
Federal Register, Volume 86 Issue 171 (Wednesday, September 8, 2021)
[Federal Register Volume 86, Number 171 (Wednesday, September 8, 2021)]
[Notices]
[Pages 50363-50365]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[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 protected], 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.
[[Page 50364]]
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 protected]. 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.
[[Page 50365]]
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, 240-402-7500, 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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