Limited Population Pathway for Antibacterial and Antifungal Drugs Guidance for Industry

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Limited Population
Pathway for Antibacterial
and Antifungal Drugs
Guidance for Industry
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
August 2020
Procedural

Limited Population
Pathway for Antibacterial
and Antifungal Drugs
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
and/or
Office of Communication, Outreach, and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, Room 3128
Silver Spring, MD 20993-0002
Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
August 2020
Procedural

Contains Nonbinding Recommendations
TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
III. 	LPAD PATHWAY DEFINED ......................................................................................... 3
A. 	Drug Intended to Treat a Serious or Life-Threatening Infection in a Limited Population of
Patients With Unmet Needs .......................................................................................................... 3
1. Treat a Serious or Life-Threatening Infection ................................................................................. 3
2. Limited Population .......................................................................................................................... 4
3. Unmet Need...................................................................................................................................... 4
B. 	Standards for Approval Are Met ................................................................................................. 5
IV. 	RELATIONSHIP TO OTHER PROGRAMS ............................................................... 5
V. 	CONSIDERATIONS FOR APPROVAL OF DRUGS UNDER THE LPAD
PATHWAY........................................................................................................................ 6
VI. 	PROCESS FOR THE LPAD PATHWAY ..................................................................... 8
A. 	Advice .............................................................................................................................................. 8
B. 	Written Request for Approval Under the LPAD Pathway ........................................................ 9
VII. 	CONDITIONS OF APPROVAL UNDER THE LPAD PATHWAY........................... 9
A. 	Labeling .......................................................................................................................................... 9
1. Carton Labeling and Immediate Container Label ......................................................................... 10
2. Prescribing Information................................................................................................................. 10
a. 	Highlights of Prescribing Information .................................................................................... 10
b. 	Full Prescribing Information ................................................................................................... 11
3. Patient Labeling ............................................................................................................................. 12
B. 	Promotional Material .................................................................................................................. 12
C. 	Termination of Limitations ......................................................................................................... 13

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Limited Population Pathway
for Antibacterial and Antifungal Drugs
Guidance for Industry1
This guidance represents the current thinking of the Food and Drug Administration (FDA or
Agency) on this topic. It does not establish any rights for any person and is not binding on FDA
or the public. You can use an alternative approach if it satisfies the requirements of the
applicable statutes and regulations. To discuss an alternative approach, contact the FDA office
responsible for this guidance as listed on the title page.
I. 	INTRODUCTION
This guidance provides information on the implementation of section 506(h) of the Federal Food,
Drug, and Cosmetic Act (FD&C Act), added by section 3042 of the 21st Century Cures Act,2
which established the limited population pathway for antibacterial and antifungal drugs (LPAD
pathway).3
Section 506(h)(5) of the FD&C Act requires FDA to issue guidance “describing criteria,
processes, and other general considerations for demonstrating the safety and effectiveness of
limited population antibacterial and antifungal drugs.” This guidance provides this information
and is intended to assist sponsors4 in the development of certain new antibacterial and antifungal
drugs for approval under the LPAD pathway. This guidance also is intended to assist applicants
1 This guidance has been prepared by the Office of Infectious Diseases and Office of New Drug Policy in the Center
for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) at the
Food and Drug Administration.
2 Public Law 114-255, 130 Stat. 1033 (2016) (21 U.S.C. 356).
3 For the purposes of this guidance, all references to drugs, drug products, and products include both human drug
and biological products regulated by CDER and CBER unless otherwise specified.
4 For purposes of this guidance, the term sponsor and applicant includes any sponsor of an investigational new drug
application (IND) or applicant for a new drug application or biologics license application under section 505 of the
FD&C Act or section 351 of the Public Health Service Act, respectively.

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in developing labeling, including prescribing information, patient labeling, and carton/container
labeling, that incorporates certain statements required by section 506(h).5
This guidance does not address specific recommendations on the design of clinical trials for
drugs developed under the LPAD pathway. That topic is addressed in the guidance for industry
Antibacterial Therapies for Patients With an Unmet Medical Need for the Treatment of Serious
Bacterial Diseases (August 2017) (Unmet Medical Need guidance).
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
as recommendations, unless specific regulatory or statutory requirements are cited. The use of
the word should in Agency guidances means that something is suggested or recommended, but
not required.
II. 	BACKGROUND
The decline in antibacterial drug research and development as serious antibacterial drug resistant
infections increase is a critical public health and patient care concern. As described in the Unmet
Medical Need guidance, there are a number of challenges associated with conducting clinical
trials to evaluate antibacterial drugs for the treatment of patients with serious bacterial diseases.6
Similar challenges are also associated with the development of new antifungal drugs for the
treatment of serious fungal diseases.
Title VIII of the Food and Drug Administration Safety and Innovation Act, titled Generating
Antibiotic Incentives Now (GAIN), added section 505E to the FD&C Act (21 U.S.C. 355f),
offering incentives for the development of antibacterial and antifungal drug products that treat
serious or life-threatening infections. Even with these incentives, challenges remain. FDA is
committed to using the tools at its disposal, including the LPAD pathway, to help encourage the
development of safe and effective drug products that address unmet needs of patients with
serious bacterial and fungal infections.
5 Except in certain instances discussed in this guidance, the statutory LPAD pathway framework does not alter the
statutory or regulatory requirements for drugs, nor does it affect the recommendations or the applicability of FDA’s
guidance documents, including the guidance for industry Microbiology Data for Systemic Antibacterial Drugs —
Development, Analysis, and Presentation (February 2018). We update guidances periodically. To make sure you
have the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents.
6 For purposes of this guidance, FDA considers infections to be types of diseases or conditions. The terms
condition, disease, and infection are used interchangeably.

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III. 	LPAD PATHWAY DEFINED
Section 506(h)(1) of the FD&C Act provides that FDA may approve an antibacterial or
antifungal drug,7 alone or in combination with one or more other drugs, under the LPAD
pathway, if the following apply:
• 	The drug is intended to treat a serious or life-threatening infection in a limited population
of patients with unmet needs;
• 	The standards for approval under section 505(c) and (d) of the FD&C Act (21 U.S.C.
355) or the standards for licensure under section 351 of the Public Health Service Act
(PHS Act) (42 U.S.C. 262), as applicable, are met; and
• 	FDA receives a written request from the sponsor to approve the drug as a limited
population drug (see section VI.B., Written Request for Approval Under the LPAD
Pathway).
As discussed in greater detail in section V., Considerations for Approval of Drugs Under the
LPAD Pathway, development programs for drugs eligible for approval under the LPAD pathway
may follow the streamlined approaches described in the Unmet Medical Need guidance. A
streamlined clinical development program for a limited population may involve smaller, shorter,
or fewer clinical trials. FDA encourages sponsors to discuss with FDA their proposed designs of
streamlined clinical trials early in the process.
Section 506(h)(3) also imposes specific labeling requirements and a requirement for
presubmission of promotional materials for drugs approved under the LPAD pathway.
There may be cases when a drug is approved under the LPAD pathway for certain indications
and may be approved under a non-LPAD pathway for other indications. The labeling will make
clear the indications approved under the LPAD pathway (see section VII., Conditions for
Approval Under the LPAD Pathway).
A. 	Drug Intended to Treat a Serious or Life-Threatening Infection in a Limited
Population of Patients With Unmet Needs
1. 	Treat a Serious or Life-Threatening Infection
To be eligible for approval via the LPAD pathway under section 506(h)(1) of the FD&C Act, a
drug must be intended to treat a serious or life-threatening infection. FDA interprets the terms
serious and life threatening in this provision to have the same meanings as they do under 21 CFR
312.300(b)(1) and 21 CFR 312.81(a), respectively. These definitions are described further in the
7 Some drugs that are intended to treat a serious or life-threatening infection may not be antibacterial or antifungal
drugs, in which case they would not be eligible for the LPAD pathway. See section 506(h)(1) of the FD&C Act.
Sponsors with questions regarding whether a drug is considered an antibacterial or antifungal drug for purposes of
LPAD pathway eligibility should contact the relevant review division or office in CDER or CBER, as applicable.

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guidance for industry Expedited Programs for Serious Conditions — Drugs and Biologics (May
2014) (Expedited Programs guidance).
FDA considers a drug to be intended to treat a serious or life-threatening disease or condition if
the drug is intended to have an effect on a serious condition or a serious aspect of the serious or
life-threatening condition, such as a direct effect on a serious manifestation or symptom of a
condition or other intended effects.8 This direct effect may include diagnosing, preventing,
and/or treating a serious aspect of the condition. Accordingly, FDA intends to consider a drug to
treat a serious or life-threatening infection if the drug diagnoses, prevents, or treats such an
infection.
2. 	Limited Population
To be eligible for approval via the LPAD pathway under section 506(h)(1) of the FD&C Act, a
drug must be intended for use in a limited population of patients. FDA interprets limited
population of patients in this provision to mean a group of patients that is limited in a way that is
clinically relevant to health care providers.9 The labeling should define the limited population
that the drug is intended to treat so that a health care provider would be able to identify the
patients in the clinical setting for whom FDA determined the benefits of the drug outweigh its
risks. A limited population may be a defined subset of a broader population of patients for
whom the drug could potentially be effective or, in some cases, may be the only population of
patients for whom the drug may be effective because of its narrow spectrum of activity.10
As noted above, FDA may consider certain drugs that prevent a serious or life-threatening
infection to be eligible for approval under the LPAD pathway. For preventive drugs, FDA
intends to evaluate the population of patients for which the drug is intended to be prescribed, not
the expected incidence of the infection that the drug is intended to prevent, in determining
whether the population is limited in a clinically relevant way, as described above. In general,
FDA does not intend to consider a population to be limited in a way that is clinically relevant
simply because a serious infectious disease that a drug is intended to prevent may occur
infrequently or even rarely. For example, an antibacterial drug that would have a role in the
preventive armamentarium for only a select patient population (e.g., mechanically ventilated
patients) with no other options may be an appropriate candidate for the LPAD pathway; in
contrast, an antibacterial drug intended for broad population-level prevention of an infrequently
or rarely occurring serious or life-threatening disease generally would not be an appropriate
candidate for the LPAD pathway.
3. 	Unmet Need
To be eligible for approval via the LPAD pathway under section 506(h)(1) of the FD&C Act, a
drug must be intended for use by patients with unmet needs. FDA interprets the term unmet need
8 This is consistent with the Expedited Programs guidance.
9 The intended patient population does not need to be below a specific numerical threshold.
10 See section V., Considerations for Approval of Drugs Under the LPAD Pathway, for illustrative examples.

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in this provision to have the same meaning as the term unmet medical need in the Expedited
Programs guidance.
The Unmet Medical Need guidance further explains the Agency’s current thinking about unmet
needs in patients who have serious bacterial diseases. The concepts described in the Unmet
Medical Need guidance also apply to antifungal therapies for patients with unmet needs for
serious fungal infections.
B. 	Standards for Approval Are Met
An applicant must provide in its application substantial evidence of effectiveness for the drug’s
intended use and sufficient information to conclude that the drug is safe for use under the
conditions prescribed, recommended, or suggested in the proposed labeling.11 For additional
information, see section V., Considerations for Approval of Drugs Under the LPAD Pathway.
The rules of construction set forth in section 506(h)(8) of the FD&C Act reiterate that the LPAD
pathway provision does not alter FDA approval standards under the FD&C Act or the PHS Act,
including the standards of evidence and applicable conditions for approval under these Acts.
The provision also does not alter the authority of FDA to monitor drugs pursuant to these Acts.
IV. 	RELATIONSHIP TO OTHER PROGRAMS
An applicant seeking approval of a drug under the LPAD pathway is not precluded from seeking
designation or approval under any other applicable provision in the FD&C Act or PHS Act for
which the drug otherwise qualifies (e.g., fast track designation, breakthrough therapy
designation, regenerative medicine advanced therapy designation, accelerated approval, priority
review designation).12 An applicant that seeks approval of a drug under the LPAD pathway may
also seek designation, as applicable, under other programs, including qualified infectious disease
product designation under the GAIN provisions13 or orphan drug designation.14
11 See sections 505(d)(1) and (5) of the FD&C Act. For a biological product to be licensed under section 351 of the
PHS Act, a sponsor must demonstrate that its product is safe, pure, and potent. Potency has long been interpreted to
include effectiveness (21 CFR 600.3(s)).
12 Section 506(h)(4) of the FD&C Act. Sponsors should consult the Expedited Programs guidance for generally
applicable information about, the criteria for, and the benefits of FDA’s expedited programs. See also the guidance
for industry Expedited Programs for Regenerative Medicine Therapies for Serious Conditions (February 2019) for
information about the regenerative medicine advanced therapy designation program and the application of other
expedited programs to regenerative medicine therapies.
13 Section 505E of the FD&C Act (21 U.S.C. 355f).
14 Section 526 of the FD&C Act (21 U.S.C. 360bb).

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V. 	CONSIDERATIONS FOR APPROVAL OF DRUGS UNDER THE LPAD
PATHWAY
As discussed above, for an applicant to obtain approval of a drug under the LPAD pathway, the
drug must meet the statutory standards for approval under section 505 of the FD&C Act or
section 351 of the PHS Act, as applicable. The LPAD pathway requires that FDA’s
determination of safety and effectiveness take into account the severity, rarity, or prevalence of
the infection a drug is intended to treat and the lack of alternative treatment in the limited
population for which the drug is intended.15 FDA may approve a drug under the LPAD pathway
based upon a conclusion of a positive benefit-risk balance in the limited population, even though
insufficient data exist to conclude that there is a favorable benefit-risk profile in a broader
population.16 As discussed in the Unmet Medical Need guidance, drugs with risks that would be
unacceptable for a broad population may be acceptable for patient populations with serious
diseases that do not have other treatment options. Acceptance of greater uncertainty or higher
risk in patients with serious diseases and with unmet needs (such as those in the limited
population targeted) is an appropriate approach to the benefit-risk assessment.17 Compliance
with the labeling and promotional material requirements in section 506(h)(3) can help the health
care community understand that the drug was approved under a pathway in which benefits and
risks were assessed in this manner.
The LPAD pathway should not be used to manage known or potential serious risks associated
with a drug that may be addressed using other authorities under the FD&C Act or the PHS Act, if
applicable.18 The LPAD pathway should also not be used to salvage a trial that fails to
demonstrate its objective (e.g., the LPAD pathway is generally not appropriate for submission of
results of subpopulations from trials failing to meet their primary endpoint) or an inadequately
designed development program.
If an applicant submits a request for approval of an application under the LPAD pathway, but the
drug instead can be approved under the traditional approval pathway or the accelerated approval
pathway alone, FDA will approve the application, but not under the LPAD pathway. For
example, a drug for which the sponsor conducts a streamlined development program may be
eligible for traditional approval if the clinical data support approval in a broader population.
When reviewing an application submitted under the LPAD pathway, FDA will take into account
the severity, rarity, or prevalence of the infection that the drug is intended to treat and the
15 See section 506(h)(2) of the FD&C Act.
16 Ibid.
17 See 21 CFR 312.80, subpart E, Drugs Intended to Treat Life-Threatening and Severely-Debilitating Illnesses. See
also the Unmet Medical Need guidance.
18 For example, see section 505-1 of the FD&C Act (21 U.S.C. 355-1).

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availability or lack of alternative treatment for the limited population.19 Required labeling
statements help ensure that the health care providers understand the limited population of
patients for whom the drug is intended and the limitations associated with streamlined
development programs that will often support LPAD pathway approval (see section VII.,
Conditions for Approval Under the LPAD Pathway).20 The conditions for approval under the
LPAD pathway, including the labeling requirements, which can facilitate such health care
provider understanding, will be taken into consideration by FDA in its benefit-risk assessment.
As discussed in section III., LPAD Pathway Defined, development programs for drugs eligible
for approval under the LPAD pathway may follow the streamlined approaches described in the
Unmet Medical Need guidance, such as the following:
• 	A clinical trial using noninferiority designs, including a single noninferiority trial at a
body site of infection, which might include wider noninferiority margins than used in
traditional development programs, or
• 	A superiority clinical trial in a limited population nested within a noninferiority clinical
trial in a broader population.
A streamlined clinical development program for a limited population may involve smaller,
shorter, or fewer clinical trials. In such circumstances, robust nonclinical evaluations (including
animal models of infection) and pharmacokinetic/pharmacodynamic data may provide important
information to help assess the benefits and risks of the drug in the intended limited population.21
Some examples of drugs for which approval under the LPAD pathway could be appropriate,
assuming the statutory criteria are met, include the following: 22
• 	An antibacterial drug with a narrow spectrum of activity (e.g., active against only a single
species (or a few species) within a genus) intended to treat a limited patient population
with a serious infection that is infrequently caused by the target pathogen or pathogens,23
and
19 Section 506(h)(2) of the FD&C Act. As discussed above, if a preventive drug’s intended population is broad,
FDA may not consider the drug to be intended to treat a limited population of patients, even if the infection occurs
rarely.
20 Section 506(h)(3)(A) of the FD&C Act.
21 See the Unmet Medical Need guidance at page 4.
22 Approved LPAD pathway drugs can be found on the FDA web page Limited Population Pathway for
Antibacterial and Antifungal Drugs — the LPAD Pathway at https://www.fda.gov/drugs/development-
resources/limited-population-pathway-antibacterial-and-antifungal-drugs-lpad-pathway.
23 For further discussion regarding development of antibacterial drugs active against only a single species, see the
Antimicrobial Drugs Advisory Committee meeting materials for April 13, 2017, available at
https://www.fda.gov/advisory-committees/advisory-committee-calendar/april-13-2017-meeting-antimicrobial-drugs-
advisory-committee-meeting-announcement-04122017-04122017.

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• 	An antibacterial or antifungal drug that, based on available therapy, would only have a
role in the therapeutic armamentarium for a select patient population with limited or no
other treatment options.24
The Unmet Medical Need guidance further explains FDA’s current thinking about possible
streamlined development programs and clinical trial designs for antibacterial drugs to treat
serious bacterial diseases with unmet medical needs, including when patients have a serious
bacterial disease for which effective antibacterial drugs are limited or lacking. The concepts
described in the Unmet Medical Need guidance are applicable to drugs that are eligible for the
LPAD pathway. Sponsors should consult the Unmet Medical Need guidance for further
information about these potential development programs.
VI. 	PROCESS FOR THE LPAD PATHWAY
A. 	Advice
FDA anticipates that early and frequent communications between the Agency and sponsors
interested in pursuing approval for their drugs under the LPAD pathway can help reduce overall
drug development timelines. Pursuant to the requirement to provide prompt advice to sponsors
of drugs seeking approval under the LPAD pathway,25 FDA encourages sponsors to
communicate with the Agency early in development regarding the planned development
program.26 Sponsors interested in the LPAD pathway should clearly state their intentions during
discussions with FDA.
Depending on the proposed development program and available clinical data, FDA may be able
to provide advice on potential eligibility for the LPAD pathway early in clinical development.
However, results of the clinical trials intended to support approval of the application may change
the Agency’s conclusions about the benefits and risks of a drug and its eligibility for approval
under the LPAD pathway. Furthermore, the approval of other drugs or other changes to
available therapy may affect the Agency’s determination of whether a drug addresses an unmet
need. Accordingly, although FDA may provide advice on potential eligibility, FDA intends to
make the determination of whether a drug meets the criteria for the LPAD pathway at the time of
the drug’s approval.
If a sponsor intends to request that a drug be approved under the LPAD pathway, FDA
recommends that the sponsor include this request as a topic of discussion at the presubmission
(pre-new drug application (pre-NDA) or pre-biologics license application (pre-BLA)) meeting.
24 For example, the drug product pretomanid tablets was approved under the LPAD pathway on August 14, 2019, for
use in combination with bedaquiline and linezolid for the treatment of adults with pulmonary extensively drug
resistant or treatment-intolerant or nonresponsive multidrug-resistant tuberculosis. This patient population has
unmet needs. See FDA’s Drug Approval Package: Pretomanid web page at
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000TOC.cfm.
25 Section 506(h)(6) of the FD&C Act.
26 See the Unmet Medical Need guidance.

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Following such discussion, if a sponsor seeks approval under the LPAD pathway, such a request
must be made in writing with the NDA or BLA submission, as specified below.27
B. 	Written Request for Approval Under the LPAD Pathway
Section 506(h)(1)(C) of the FD&C Act requires a sponsor to submit a written request for FDA to
approve a drug under the LPAD pathway. The applicant should submit the written request with
the original NDA, BLA, or efficacy supplement, but FDA could accept the request at any time
during the review of the application. If FDA concludes during its review of an application that
the LPAD pathway would be appropriate for a drug and the applicant has not submitted a written
request for approval under the LPAD pathway, FDA will communicate its recommendation to
the applicant.
Written requests for approval under the LPAD pathway should contain the following
information:
• 	Identification of the submission in the cover letter as “REQUEST FOR LPAD
APPROVAL”;
• 	The specific serious or life-threatening infection that the drug is intended to treat; if
multiple indications are sought, specify which indications are proposed for approval
under the LPAD pathway;
• 	The limited population of patients with unmet needs for whom the drug is intended; and
• 	A concise summary of how the conditions of approval under the LPAD pathway (see
section VII., Conditions of Approval Under the LPAD Pathway) affect the benefit-risk
assessment of the drug.
VII. 	CONDITIONS OF APPROVAL UNDER THE LPAD PATHWAY
A. 	Labeling
Drugs approved under the LPAD pathway are required under section 506(h)(3)(A) of the FD&C
Act to include certain labeling statements to convey to the health care community28 that the drug
has been shown to be safe and effective for use only in a limited population. To make fully
informed decisions, the health care community should understand that approval of a drug under
the LPAD pathway was based on a benefit-risk assessment that more flexibly accounted for the
severity, rarity, or prevalence of the infection the drug is intended to treat and the lack of
alternatives available for the patient population.
27 Section 506(h)(1)(C) of the FD&C Act.
28 For purposes of this guidance, the term health care community includes health care providers and patients and
their families or caregivers.

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Section 506(h)(3)(A)(i) of the FD&C Act requires all labeling and advertising of a drug
approved under the LPAD pathway to contain the statement “Limited Population” in a prominent
manner and adjacent to, but not more prominent than, the proprietary name of such drug, if any,
or, if there is no proprietary name, the established name of the drug product as defined in section
502(e)(3) of the FD&C Act (21 U.S.C. 352) or, in the case of a biologic product, the proper
name. In most cases, to fulfill the prominence requirement, the font size, typeface, case, and
bolding should match that of the adjacent proprietary name (or nonproprietary name if there is no
proprietary name).
Section 506(h)(3)(A)(ii) of the FD&C Act requires the prescribing information of drugs
approved under the LPAD pathway to include the statement: “This drug is indicated for use in a
limited and specific population of patients.”
Below are further recommendations about the “Limited Population” statements and the
requirements for specific types of labeling.
If approval under the LPAD pathway is sought for fewer than all indications when multiple
indications are approved or proposed, we recommend that applicants consult the review division
for advice regarding how to incorporate LPAD pathway-related information into labeling.
1. 	Carton Labeling and Immediate Container Label
The statement “Limited Population” should be included on the principal display panel of the
product carton(s) and, if space permits,29 immediate containers, adjacent to the proprietary name
(or nonproprietary name if there is no proprietary name) in a manner that is consistent with the
requirements outlined above. In cases where the product is available as a dosage form with only
a container label (no carton labeling), the “Limited Population” statement should be included on
the principal display panel of the container label, adjacent to the proprietary name (or
nonproprietary name if there is no proprietary name). To provide clarity, FDA recommends
including an asterisk next to the “Limited Population” statement with a footnote at the bottom of
the principal display panel,30 stating: “See prescribing information for [drug name] for
information about the limited population.”31
2. 	Prescribing Information
a. 	Highlights of Prescribing Information
In the Highlights of Prescribing Information (Highlights), on the line immediately beneath the
statement “Initial U.S. Approval,” the statement “LIMITED POPULATION” should appear in
uppercase letters and bold print.
29 See 21 CFR 210.10(i) for additional information about packaging that is too small for the additional statements.
30 This could also be on a side panel if space limitations preclude placement on the principal display panel.
31 If the drug is approved for multiple indications, some of which are approved under the LPAD pathway and some
are not, the language could instead read: “See prescribing information for [drug name] for information about the
indicated populations.”

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Under the INDICATIONS AND USAGE heading in the Highlights, the statement “Limited
Population” should be included in the same font size, typeface, and case as the proprietary name
(or nonproprietary name if there is no proprietary name) before each indication approved under
the LPAD pathway.
Drugs approved under the LPAD pathway must include the following statement in the
prescribing information: “This drug is indicated for use in a limited and specific population of
patients.”32 In the Highlights, FDA recommends that this statement be included at the end of
each indication approved under the LPAD pathway. If all indications for a drug were approved
under the LPAD pathway, the statement “This drug is indicated for use in a limited and specific
population of patients” can be a standalone bullet point preceding the indications instead of being
repeated in each indication. In the Highlights, indications for drugs approved under the LPAD
pathway should also convey the patient population for which the drug is approved (e.g., the
patient population with a serious infection caused by a bacterial or fungal pathogen for which the
patient has limited therapeutic options) as discussed in the Unmet Medical Need guidance. For
example:
• 	LIMITED POPULATION: MYDRUG is a (established pharmacologic class) indicated,
in adults who have limited or no alternative treatment options, for the treatment of
Disease-Y caused by designated susceptible microorganisms. This drug is indicated for
use in a limited and specific population of patients. (1.x)
b. 	Full Prescribing Information
In the INDICATIONS AND USAGE section in the Full Prescribing Information, the statement
“Limited Population” should be included in the same font size, typeface, and case as the
proprietary name (or nonproprietary name if there is no proprietary name) before each indication
approved under the LPAD pathway.
Labeling for drugs approved under the LPAD pathway must include the following statement:
“This drug is indicated for use in a limited and specific population of patients.”33 In the Full
Prescribing Information, FDA recommends that this statement be included in the
INDICATIONS AND USAGE section at the end of each indication approved under the LPAD
pathway. For drugs approved under the LPAD pathway, the indication should also convey the
population of patients for whom the drug is approved (e.g., the population of patients who have a
serious infection caused by a bacterial or fungal pathogen for which the patient has limited
therapeutic options) and may summarize the limitations of the available data that supported the
approval. For example:34
32 Section 506(h)(3)(A)(ii) of the FD&C Act.
33 Section 506(h)(3)(A)(ii) of the FD&C Act.
34 This is an example and the language may be adjusted or changed as necessary.

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• 	LIMITED POPULATION: MYDRUG is indicated in adults who have limited or no
alternative treatment options for the treatment of Disease-Y caused by the following
susceptible gram-negative microorganisms: [Genus species #1, Genus species #2, etc.].
Approval of this indication is based on limited clinical safety and effectiveness data.
This drug is indicated for use in a limited and specific population of patients.
3. 	Patient Labeling
If FDA-approved patient labeling is required or recommended for the drug, the statement
“Limited Population” should be included before the proprietary name in the drug title (or
nonproprietary name if there is no proprietary name) of the patient package insert, Instructions
for Use, and/or Medication Guide. The font size, typeface, case, and bolding of “Limited
Population” should match that of the adjacent proprietary name (or nonproprietary name if there
is no proprietary name). FDA recommends including an asterisk next to the “Limited
Population” statement that corresponds to the statement explained below.
For example: LIMITED POPULATION*: MYDRUG ( mye-drug)
*[DrugName] was approved by FDA using the Limited Population pathway. FDA has approved
this drug for a limited and specific population of patients that have few or no other options.
B. 	Promotional Material
Under section 506(h)(3)(B) of the FD&C Act, an applicant of a drug approved under the LPAD
pathway must submit copies of all promotional materials related to the LPAD pathway drug at
least 30 calendar days before dissemination of materials (predissemination). In addition, section
506(h)(3)(A)(i) requires promotional materials, including promotional labeling and advertising,
to include the statement “Limited Population” in a prominent manner and adjacent to, but not
more prominent than, the proprietary name of such drug, if any, or if there is no proprietary
name, the established name of the drug product as defined in section 502(e)(3) of the FD&C Act
(21 U.S.C. 352) or, in the case of a biologic product, the proper name. The applicant of a drug
approved under the LPAD pathway must also ensure that promotional materials are truthful and
nonmisleading, as required under the FD&C Act and FDA’s implementing regulations.35
Applicants may apply the recommendations in section VII.A., Labeling, to their promotional
materials.
The following procedural outline is designed to assist applicants in satisfying the 30-calendar-
day predissemination requirement. These procedures are, in part, adapted from the Agency’s
guidance for industry Providing Regulatory Submissions in Electronic and Non-Electronic
35 See, e.g., sections 201(n), 502(a), and 502(n) of the FD&C Act and 21 CFR 1.21 and 202.1(e)(5). The Office of
Prescription Drug Promotion within CDER or the Advertising and Promotional Labeling Branch in CBER is the
primary office dedicated to the review and enforcement of these requirements.

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Format—Promotional Labeling and Advertising Materials for Human Prescription Drugs (June
2019) (e-Sub guidance).36
Applicants should do the following to meet the predissemination requirement for LPAD pathway
drugs:
• 	Prepare draft promotional materials and submit those materials to the Agency as
described in the e-Sub guidance section IV.C. Applicants should review section IV.C. of
the e-Sub guidance for accompanying information for the submission. Applicants should
also note on their accompanying correspondence to the Office of Prescription Drug
Promotion in the Center for Drug Evaluation and Research that the submission is for a
“Pre-Submission of Promotional Materials for a Limited Population Pathway
Antibacterial or Antifungal Drug.”
• 	Upon receipt of a complete submission by the Agency, the 30-calendar-day
predissemination clock will begin. This is calendar day 1. After 30 calendar days, or
calendar day 31, the statutory predissemination requirement will be satisfied.
While the above procedure satisfies an applicant’s statutory obligation at section 506(h)(3)(B) of
the FD&C Act, applicants must still comply with all other statutory and regulatory requirements
for promotional materials, including that their materials be truthful and nonmisleading.
Furthermore, applicants must comply with the postmarketing requirements under the FD&C Act
and implementing regulations, which require that all prescription drug product applicants submit
labeling or advertising devised for promotion of the drug product at the time of initial
dissemination or publication (21 CFR 314.81(b)(3)(i) and 21 CFR 601.12(f)(4)).37
C. 	Termination of Limitations
Under section 506(h)(7) of the FD&C Act, FDA may terminate the limitations associated with an
LPAD pathway approval for an individual drug or indication upon approval of a subsequent
supplement, when FDA has determined that clinical data demonstrate that the drug is safe and
effective for a broader indication.38 Additional clinical data should enable FDA to conclude that
the labeling and other conditions of the LPAD pathway approval are no longer necessary for the
drug product.39 When determining whether limitations should be terminated for a drug approved
under the LPAD pathway, FDA intends to consider any differences regarding the indicated
patient populations; conditions of use; and dosage, duration, and strength between the proposed
broader indication and the indication approved under the LPAD pathway. FDA encourages
36 For more information, see the e-Sub guidance.
37 For information related to fulfilling the postmarketing requirement for promotional materials, see the e-Sub
guidance at section IV.A.
38 Postmarketing studies are not required under the LPAD pathway. An applicant can choose to pursue a broader
indication, if warranted, for a drug or indication approved under the LPAD pathway.
39 Section 506(h)(7) of the FD&C Act.

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applicants to discuss with the Agency the design of clinical trials and types of evidence intended
to support termination of LPAD pathway limitations.
An applicant submitting an efficacy supplement to support termination of LPAD pathway
limitations should identify the submission in the cover letter as “REQUEST FOR
TERMINATION OF LPAD PATHWAY LIMITATIONS.” If LPAD pathway limitations are
terminated, FDA will indicate the termination in the approval letter. Upon approval, the LPAD
pathway language will be removed from the labeling (e.g., the statement “Limited Population”
will be removed from all the approved labeling and the sentence “This drug is indicated for use
in a limited and specific population of patients” will be removed from the INDICATIONS AND
USAGE section). Upon approval of such a supplement, the presubmission of promotional
materials under section 506(h)(3)(B) of the FD&C Act will no longer be required.