0765_Agency Guidance

Expedited Programs for Serious Conditions-Drugs and Biologics

0765_Agency Guidance

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Guidance for Industry
Expedited Programs for Serious
Conditions – Drugs and
Biologics

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)
May 2014
Procedural
OMB Control No. 0910-0765
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See additional PRA statement in section X of this guidance.

Guidance for Industry
Expedited Programs for Serious
Conditions – Drugs and
Biologics
Additional copies are available from:
Office of Communications
Division of Drug Information, WO51, Room 2201
Center for Drug Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Silver Spring, MD 20993
Phone: 301-796-3400; Fax: 301-847-8714
druginfo@fda.hhs.gov
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

and/or
Office of Communication, Outreach and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., WO71, Room 3128
Silver Spring, MD 20993
Phone: 800-835-4709 or 240-402-7800
ocod@fda.hhs.gov
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

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)
May 2014
Procedural

Contains Nonbinding Recommendations
TABLE OF CONTENTS
I.

INTRODUCTION............................................................................................................. 1

II.

BACKGROUND ............................................................................................................... 1

III.

CONCEPTS FOR EXPEDITED PROGRAMS............................................................. 2

Serious Condition ........................................................................................................................... 2

Available Therapy.......................................................................................................................... 3

Unmet Medical Need...................................................................................................................... 4

IV.

OVERVIEW OF EXPEDITED PROGRAMS ............................................................... 7

FAST TRACK DESIGNATION ..................................................................................... 9
A.

Qualifying Criteria for Fast Track Designation.......................................................................... 9

Features of Fast Track Designation ............................................................................................. 9

VI.

BREAKTHROUGH THERAPY DESIGNATION ..................................................... 10

Qualifying Criteria for Breakthrough Therapy Designation................................................... 10

Features of Breakthrough Therapy Designation ...................................................................... 13

VII.

ACCELERATED APPROVAL..................................................................................... 15

Qualifying Criteria for Accelerated Approval .......................................................................... 16

Accelerated Approval Endpoints................................................................................................ 17

Evidentiary Criteria for Accelerated Approval ........................................................................ 19

Conditions of Accelerated Approval .......................................................................................... 22

VIII. PRIORITY REVIEW DESIGNATION ....................................................................... 24
A.

Qualifying Criteria for Priority Review Designation ............................................................... 24

Features of Priority Review Designation ................................................................................... 25

IX.

GENERAL CONSIDERATIONS ................................................................................. 25

Manufacturing and Product Quality Considerations ............................................................... 25

Nonclinical Considerations ......................................................................................................... 26

Clinical Inspection Considerations ............................................................................................. 27

Companion Diagnostics ............................................................................................................... 27

PAPERWORK REDUCTION ACT OF 1995 .............................................................. 27

APPENDIX 1: PROCESSES FOR FAST TRACK, BREAKTHROUGH THERAPY, AND
PRIORITY REVIEW DESIGNATIONS ................................................................................. 28
A.

Process for Fast Track Designation............................................................................................ 28

Process for Breakthrough Therapy Designation....................................................................... 30

Contains Nonbinding Recommendations
C.

Process for Priority Review Designation ................................................................................... 33

APPENDIX 2: PROCESSES FOR ROLLING REVIEW ...................................................... 35
A.

Agreement on Proposal ............................................................................................................... 35

Portions of an Application Eligible for Early Submission ....................................................... 35

Submission of User Fees .............................................................................................................. 36

Commencement of Review .......................................................................................................... 36

Calculation of Review Time ........................................................................................................ 36

Contains Nonbinding Recommendations

Guidance for Industry1
Expedited Programs for Serious Conditions – Drugs and Biologics
This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes
and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for
implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate
number listed on the title page of this guidance.

INTRODUCTION

The following four FDA programs are intended to facilitate and expedite development and
review of new drugs 2 to address unmet medical need in the treatment of a serious or lifethreatening 3 condition: fast track designation, breakthrough therapy designation, accelerated
approval, and priority review designation (see section IV for an overview of the programs). The
purpose of this guidance for industry is to provide a single resource for information on FDA’s
policies and procedures for these four programs as well as threshold criteria generally applicable
to concluding that a drug is a candidate for these expedited development and review programs.
FDA’s guidance documents, including this guidance, 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 programs described in this guidance are intended to help ensure that therapies for serious
conditions are approved and available to patients as soon as it can be concluded that the
therapies’ benefits justify their risks. The Agency first formally articulated its thinking on
expediting the availability of promising new therapies in regulations codified at part 312, subpart
E ( 21 CFR part 312). 4 The subpart E regulations are intended to speed the availability of new
therapies to patients with serious conditions, especially when there are no satisfactory alternative
therapies, while preserving appropriate standards for safety and effectiveness. The regulations
1

This guidance has been prepared by the Center for Drug Evaluation and Research (CDER) in cooperation with the
Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration.
2
For the purposes of this guidance, all references to drugs or drug products include both human drugs and
biological drug products regulated by CDER and CBER unless otherwise specified.
3
Whether a Condition Is Serious explains that all references to serious conditions include life-threatening
conditions.
4
Food and Drug Administration, Interim Rule, Investigational New Drug, Antibiotic, and Biological Drug Product
Regulations; Procedures for Drugs Intended to Treat Life-Threatening and Severely Debilitating Illnesses (53 FR
41516, October 21, 1988).
1

Contains Nonbinding Recommendations
call for earlier attention to drugs that have promise in treating such conditions, including early
consultation with FDA for sponsors of such products and efficient trial design, potentially
relying on well-controlled phase 2 studies for evidence of effectiveness. The subpart E
regulations specifically recognize that patients and physicians are generally willing to accept
greater risks and side effects from treatment of life-threatening and severely debilitating diseases
than they would for other diseases. The four principal programs that support these principles are
fast track designation, breakthrough therapy designation, accelerated approval, and priority
review designation (referred to in this guidance as the Agency’s expedited programs).
FDA has a history of applying the philosophy underlying subpart E to drugs for rare diseases
through use of the Agency’s expedited programs. FDA recognizes that certain aspects of drug
development that are feasible for common diseases may not be feasible for rare diseases and that
development challenges are often greater with increasing rarity of the disease. FDA will
continue to apply flexibility in these situations to address particular challenges posed by each
disease.
III.

CONCEPTS FOR EXPEDITED PROGRAMS

The programs that are the subject of this guidance, fast track designation, breakthrough therapy
designation, accelerated approval, and priority review, are summarized in section IV and
described individually in detail in sections V, VI, VII, and VIII. All four expedited programs
represent efforts to address an unmet medical need in the treatment of a serious condition, which
is discussed in the following paragraphs.
A.

Serious Condition

Whether a Condition Is Serious

FDA intends to interpret the term serious as it has done in the past for the purposes of
accelerated approval 5 and expanded access to investigational drugs for treatment use. 6 A serious
disease or condition is defined in the expanded access regulations as follows:
. . . a disease or condition associated with morbidity that has substantial
impact on day-to-day functioning. Short-lived and self-limiting
morbidity will usually not be sufficient, but the morbidity need not be
irreversible if it is persistent or recurrent. Whether a disease or condition
is serious is a matter of clinical judgment, based on its impact on such
factors as survival, day-to-day functioning, or the likelihood that the
disease, if left untreated, will progress from a less severe condition to a
more serious one. 7

Food and Drug Administration, Final Rule, New Drug, Antibiotic, and Biological Drug Product Regulations;
Accelerated Approval (57 FR 58942, December 11, 1992) and Food and Drug Administration, Proposed Rule, New
Drug, Antibiotic, and Biological Drug Product Regulations; Accelerated Approval (57 FR 13234, April 15, 1992).
6
Part 312, subpart I.
7
21 CFR 312.300(b)(1).
2

Contains Nonbinding Recommendations
Note: For the purposes of this guidance, the terms condition, disease, and illness are used
interchangeably. All conditions meeting the definition of life-threatening as set forth at
§ 312.81(a) would also be serious conditions.
2.

Whether the Drug Is Intended to Treat a Serious Condition

As referenced in section IV, the statutory and regulatory eligibility criteria for expedited
programs require that a drug be intended to treat a serious condition. To satisfy this criterion, a
drug must be intended to have an effect on a serious condition or a serious aspect of a condition,
such as a direct effect on a serious manifestation or symptom of a condition or other intended
effects, including the following:
x

A diagnostic product intended to improve diagnosis or detection of a serious condition in
a way that would lead to improved outcomes

A product intended to mitigate or prevent a serious treatment-related side effect (e.g.,
serious infections in patients receiving immunosuppressive therapy)

A product intended to avoid or diminish a serious adverse event associated with available
therapy for a serious condition (e.g., product that is less cardiotoxic than available cancer
therapy) 8

A product intended to prevent a serious condition or reduce the likelihood that the
condition will progress to a more serious condition or a more advanced stage of disease

Available Therapy

For purposes of this guidance, FDA generally considers available therapy (and the terms existing
treatment and existing therapy) as a therapy that:
x

Is approved or licensed in the United States for the same indication being considered for
the new drug 9 and

Is relevant to current U.S. standard of care (SOC) for the indication

Sponsors considering an expedited drug development designation or program for a drug intended to avoid a serious
adverse event associated with available therapy or diminish its severity should be aware that they will need to
provide data that directly support the effect corresponding to the level of evidence needed to meet the qualifying
criteria for the relevant designation or program (e.g., phase 3 data demonstrating lower incidence or severity of the
serious adverse reaction compared to available therapy for priority review). The requisite data may be very difficult
to obtain in early development, particularly for purposes of breakthrough therapy designation.
9
There may be a substantial number of approved therapies with varying relevance to how a serious disease is
currently treated in the United States, including therapies that are no longer used or are used rarely. Only in
exceptional cases will a treatment that is not approved for the indicated use or is not FDA-regulated (e.g., surgery)
be considered available therapy. In those cases, FDA may consider an unapproved or unlicensed therapy to
constitute available therapy if the safety and effectiveness of the use is supported by compelling evidence, including
extensive evidence in the published literature (e.g., certain well-established oncologic treatments).
3

Contains Nonbinding Recommendations
FDA’s available therapy determination generally focuses on treatment options that reflect the
current SOC for the specific indication (including the disease stage) for which a product is being
developed. In evaluating the current SOC, FDA considers recommendations by authoritative
scientific bodies (e.g., National Comprehensive Cancer Network, American Academy of
Neurology) based on clinical evidence and other reliable information that reflects current clinical
practice. When a drug development program targets a subset of a broader disease population
(e.g., a subset identified by a genetic mutation), the SOC for the broader population, if there is
one, generally is considered available therapy for the subset, unless there is evidence that the
SOC is less effective in the subset.
Over the course of new drug development, it is foreseeable that the SOC for a given condition
may evolve (e.g., because of approval of a new therapy or new information about available
therapies). FDA will determine what constitutes available therapy at the time of the relevant
regulatory decision for each expedited program a sponsor intends to use (e.g., generally early in
development for fast track and breakthrough therapy designations, at time of biologics license
application (BLA) or new drug application (NDA) submissions for priority review designation,
during BLA or NDA review for accelerated approval). FDA encourages sponsors to discuss
available therapy considerations with the Agency during interactions with FDA.
As appropriate, FDA may consult with special Government employees or other experts when
making an available therapy determination.
When determining whether a drug granted accelerated approval or approved with a risk
evaluation and mitigation strategy (REMS) that includes elements to assure safe use (ETASU)
under section 505-1 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 3551), is considered available therapy, the following principles will be applied:
x

A drug would not be considered available therapy if the drug is granted accelerated
approval based on a surrogate endpoint or an intermediate clinical endpoint and clinical
benefit has not been verified by postapproval studies. (See section III.C.3.)

A drug would be considered available therapy if the drug is granted accelerated approval
because of restricted distribution and the study population for the new drug under
development is eligible to receive the approved drug under the restricted distribution
program. Similarly, a drug would be considered available therapy if the study population
for the new drug under development is eligible to receive the approved drug under the
ETASU REMS.
C.

Unmet Medical Need

An unmet medical need is a condition whose treatment or diagnosis is not addressed
adequately by available therapy. An unmet medical need includes an immediate need
for a defined population (i.e., to treat a serious condition with no or limited treatment) or
a longer-term need for society (e.g., to address the development of resistance to
antibacterial drugs).
4

Contains Nonbinding Recommendations
1.

Where There Is No Available Therapy

If there is no available therapy for a serious condition, there is clearly an unmet medical need.
2.

Where There Is Available Therapy

When available therapy exists for a condition, a new treatment generally would be considered to
address an unmet medical need if the treatment:
x

Has an effect on a serious outcome of the condition that is not known to be influenced by
available therapy (e.g., progressive disability or disease progression when the available
therapy has shown an effect on symptoms, but has not shown an effect on progressive
disability or disease progression)

Has an improved effect on a serious outcome(s) of the condition compared with available
therapy (e.g., superiority of the new drug to available therapy when either used alone or
in combination with available therapy (i.e., as demonstrated in an add-on study))

Has an effect on a serious outcome of the condition in patients who are unable to tolerate
or failed to respond to available therapy

Can be used effectively with other critical agents that cannot be combined with available
therapy

Provides efficacy comparable to those of available therapy, while (1) avoiding serious
toxicity that occurs with available therapy, (2) avoiding less serious toxicity that is
common and causes discontinuation of treatment of a serious condition, or (3) reducing
the potential for harmful drug interactions

Provides safety and efficacy comparable to those of available therapy but has a
documented benefit, such as improved compliance, that is expected to lead to an
improvement in serious outcomes

Addresses an emerging or anticipated public health need, such as a drug shortage

In some disease settings, a drug that is not shown to provide a direct efficacy or safety advantage
over available therapy may nonetheless provide an advantage that would be of sufficient public
health benefit to qualify as meeting an unmet medical need. For example, in a condition for
which there are approved therapies that have a modest response rate or significant heterogeneity
in response, a drug with a novel mechanism of action (but comparable safety and effectiveness)
could have the potential to provide an advantage over available therapy in some patients. In such
a case, the novel mechanism of action should have a well-understood relationship to the disease
pathophysiology. In addition, there should be a reasonable basis for concluding that a significant
number of patients may respond differently to the new drug compared with available therapy.
Thus, mechanistic diversity, even without a documented efficacy or safety advantage, could be
advantageous in disease settings in which drugs become less effective or ineffective over time.
5

Contains Nonbinding Recommendations
For example, infectious disease drugs or targeted cancer therapies with novel mechanisms of
action, although appearing to have efficacy similar to available therapy across the disease
population, could benefit patients who no longer respond to available therapy. Accordingly,
FDA intends to consider a range of potential advantages over available therapy beyond those
shown in head-to-head comparisons.
3.

Where the Only Available Therapy Was Approved Under the Accelerated
Approval Program Based on a Surrogate Endpoint or an Intermediate Clinical
Endpoint and Clinical Benefit Has Not Yet Been Verified

As discussed in sections VII and III.B., FDA recognizes, as a general matter, that it is preferable
to have more than one treatment approved under the accelerated approval provisions because of
the possibility that clinical benefit may not be verified in postapproval confirmatory trials. FDA
will therefore consider products as addressing an unmet medical need if the only approved
treatments were granted accelerated approval based on a surrogate endpoint or an intermediate
clinical endpoint and clinical benefit has not been verified by postapproval studies.

Contains Nonbinding Recommendations
IV.

OVERVIEW OF EXPEDITED PROGRAMS

The table provides an overview of the four expedited programs. Additional details on the specific
programs are found in the sections that follow. Note that a drug development program may qualify
for more than one expedited program.
Comparison of FDA’s Expedited Programs for Serious Conditions
Fast Track
Breakthrough
Therapy
Nature of
Designation
Designation
program
Reference
x Section 506(b) of the
x Section 506(a) of the
FD&C Act, as added
FD&C Act, as added
by section 112 of the
by section 902 of
Food and Drug
FDASIA
Administration
Modernization Act of
1997 (FDAMA) and
amended by section
901 of the Food and
Drug Administration
Safety and Innovation
Act of 2012
(FDASIA)
Qualifying
x A drug that is
x A drug that is
criteria
intended to treat a
intended to treat a
serious condition
serious condition
AND nonclinical or
AND preliminary
clinical evidence
clinical data
demonstrate the
indicates that the drug
potential to address
may demonstrate
unmet medical need
substantial
OR
improvement on a
clinically significant
x A drug that has been
endpoint(s) over
designated as a
available therapies
qualified infectious
a
disease product

Accelerated Approval

Priority Review

Approval Pathway

Designation

x 21 CFR part 314, subpart H
x 21 CFR part 601, subpart E
x Section 506(c) of the FD&C

x Prescription Drug
User Fee Act of
1992

Act, as amended by section
901 of FDASIA

x A drug that treats a serious
condition AND generally
provides a meaningful
advantage over available
therapies AND
demonstrates an effect on a
surrogate endpoint that is
reasonably likely to predict
clinical benefit or on a
clinical endpoint that can be
measured earlier than
irreversible morbidity or
mortality (IMM) that is
reasonably likely to predict
an effect on IMM or other
clinical benefit (i.e., an
intermediate clinical
endpoint)

x An application
(original or
efficacy
supplement) for a
drug that treats a
serious condition
AND, if
approved, would
provide a
significant
improvement in
safety or
effectiveness OR
x Any supplement
that proposes a
labeling change
pursuant to a
report on a
pediatric study
under 505Ab OR
x An application for
a drug that has
been designated
as a qualified
infectious disease
productc OR
x Any application
or supplement for
a drug submitted
with a priority
review voucherd

Contains Nonbinding Recommendations
Comparison of FDA’s Expedited Programs for Serious Conditions
Accelerated Approval
Fast Track
Breakthrough
Therapy
Nature of
Designation
Designation
Approval Pathway
program
When to
x The sponsor should
x With IND or after
x With IND or after
submit request x Ideally, no later than
ordinarily discuss the
x Ideally, no later than
possibility of accelerated
the pre-BLA or prethe end-of-phase 2
approval with the review
NDA meeting
meeting
division during
development, supporting,
for example, the use of the
planned endpoint as a basis
for approval and discussing
the confirmatory trials,
which should usually be
already underway at the
time of approval
Timelines for
x Within 60 calendar
x Within 60 calendar
x Not specified
FDA response
days of receipt of the
days of receipt of the
request
request

Features

Additional
considerations

x Actions to expedite

x Intensive guidance on

x Approval based on an effect

development and
review
x Rolling review

efficient drug
development
x Organizational
commitment
x Rolling review
x Other actions to
expedite review
x Designation may be
rescinded if it no
longer meets the
qualifying criteria for
breakthrough therapyg

on a surrogate endpoint or
an intermediate clinical
endpoint that is reasonably
likely to predict a drug’s
clinical benefit

x Designation may be
rescinded if it no
longer meets the
qualifying criteria for
fast trackf

x Promotional materials
x Confirmatory trials to verify
and describe the anticipated
effect on IMM or other
clinical benefit
x Subject to expedited
withdrawal

Priority Review
Designation

x With original
BLA, NDA, or
efficacy
supplement

x Within 60
calendar days of
receipt of original
BLA, NDA, or
efficacy
supplement
x Shorter clock for
review of
marketing
application (6
months compared
with the 10-month
standard review)e

x Designation will
be assigned at the
time of original
BLA, NDA, or
efficacy
supplement filing

Title VIII of FDASIA, Generating Antibiotic Incentives Now (GAIN), provides incentives for the development of antibacterial and
antifungal drugs for human use intended to treat serious and life threatening infections. Under GAIN, a drug may be designated as a
qualified infectious disease product (QIDP) if it meets the criteria outlined in the statute. A drug that receives QIDP designation is eligible
under the statute for fast track designation and priority review. However, QIDP designation is beyond the scope of this guidance.
b Any supplement to an application under section 505 of the FD&C Act that proposes a labeling change pursuant to a report on a pediatric
study under this section shall be considered a priority review supplement per section 505A of the FD&C Act as amended by section 5(b) of
the Best Pharmaceuticals for Children Act.
c See footnote a above.
d Any application or supplement that is submitted with a priority review voucher will be assigned a priority review. Priority review
vouchers will be granted to applicants of applications for drugs for the treatment or prevention of certain tropical diseases, as defined in
section 524(a)(3) and (a)(4) of the FD&C Act and for treatment of rare pediatric diseases as defined in section 529(a)(3) of the FD&C Act.
e As part of its commitments in PDUFA V, FDA has established a review model, the Program. The Program applies to all new molecular
entity NDAs and original BLAs, including applications that are resubmitted following a Refuse-to-File action, received from October 1,
2012, through September 30, 2017. For applications filed by FDA under the Program, the PDUFA review clock will begin at the
conclusion of the 60 calendar day filing review period that begins on the date of FDA receipt of the original submission.
f A sponsor may also withdraw fast track designation if the designation is no longer supported by emerging data or the drug development
program is no longer being pursued (see section A.5. of Appendix 1).
g
A sponsor may also withdraw breakthrough therapy designation if the designation is no longer supported by emerging data or the drug
development program is no longer being pursued (see section B.5. of Appendix 1).

Contains Nonbinding Recommendations
V.

FAST TRACK DESIGNATION

Section 506(b) of the FD&C Act provides for the designation of a drug as a fast track product
“. . . if it is intended, whether alone or in combination with one or more other drugs, for the
treatment of a serious or life-threatening disease or condition, and it demonstrates the potential to
address unmet medical needs for such a disease or condition.” This provision is intended to
facilitate development and expedite review of drugs to treat serious and life-threatening
conditions so that an approved product can reach the market expeditiously. This section
describes the qualifying criteria and the features of fast track designation. Appendix 1 describes
the process for fast track designation.
A.

Qualifying Criteria for Fast Track Designation

Fast track designation applies to the drug (either alone or in combination with other drugs) and
the specific use for which it is being studied. The term drug refers to the combination of two or
more drugs if the combination is the subject of the fast track designation or request. Where
appropriate, FDA may grant designation to the development of a new use of an approved drug.
1.

Serious Condition

See section III.A.
2.

Demonstrating the Potential to Address Unmet Medical Need

The type of information needed to demonstrate the potential of a drug to address an unmet
medical need will depend on the stage of drug development at which fast track designation is
requested. Early in development, evidence of activity in a nonclinical model, a mechanistic
rationale, or pharmacologic data could be used to demonstrate such potential. Later in
development, available clinical data should demonstrate the potential to address an unmet
medical need. See section III.C.
B.

Features of Fast Track Designation

Actions to Expedite Development and Review

There are opportunities for frequent interactions with the review team for a fast track product.
These include meetings with FDA, including pre-IND meetings, end-of-phase 1 meetings, and
end-of-phase 2 meetings to discuss study design, extent of safety data required to support
approval, dose-response concerns, and use of biomarkers. Other meetings may be scheduled as
appropriate (e.g., to discuss accelerated approval, the structure and content of an NDA, and other
critical issues).
In addition, such a product could be eligible for priority review if supported by clinical data at
the time of BLA, NDA, or efficacy supplement submission (see section VIII).

Contains Nonbinding Recommendations
2.

Submission of Portions of an Application (Rolling Review)

If FDA determines, after preliminary evaluation of clinical data submitted by a sponsor, that a
fast track product may be effective, the Agency may consider reviewing portions of a
marketing application before the sponsor submits the complete application (see Appendix
2). 10
VI.

BREAKTHROUGH THERAPY DESIGNATION

Section 506(a) of the FD&C Act provides for designation of a drug as a breakthrough therapy
“. . . if the drug is intended, alone or in combination with 1 or more other drugs, to treat a serious
or life-threatening disease or condition and preliminary clinical evidence indicates that the drug
may demonstrate substantial improvement over existing therapies on 1 or more clinically
significant endpoints, such as substantial treatment effects observed early in clinical
development.” It is important to recognize that the standard for breakthrough therapy
designation is not the same as the standard for drug approval. The clinical evidence needed to
support breakthrough designation is preliminary. In contrast, as is the case for all drugs, FDA
will review the full data submitted to support approval of drugs designated as breakthrough
therapies to determine whether the drugs are safe and effective for their intended use before they
are approved for marketing. This section describes the qualifying criteria and the features of
breakthrough therapy designation. Appendix 1 describes the process for breakthrough therapy
designation.
Not all products designated as breakthrough therapies ultimately will be shown to have the
substantial improvement over available therapies suggested by the preliminary clinical evidence
at the time of designation. If the designation is no longer supported by subsequent data, FDA
may rescind the designation. 11 Because FDA commits significant resources to work particularly
closely with sponsors of breakthrough therapy products, the Agency needs to focus its resources
on breakthrough therapy drug development programs that continue to meet the program’s
qualifying criteria (see section B.5. in Appendix 1).
A.

Qualifying Criteria for Breakthrough Therapy Designation

Breakthrough therapy designation applies to the drug (either alone or in combination with other
drugs) and the specific use for which it is being studied. The term drug refers to the combination
of two or more drugs if the combination is the subject of the breakthrough therapy designation or
request. Where appropriate, FDA may grant designation to the development of a new use of an
approved drug.
1.

Serious Condition

See section III.A.

Section 506(d)(1) of the FD&C Act.
After the sponsor completes the development program, the product may still have sufficient evidence to support
marketing approval.

Contains Nonbinding Recommendations
2.

Existing (or Available) Therapies

See section III.B.
3.

Preliminary Clinical Evidence

Unlike the information that could support fast track designation, which could include theoretical
rationale, mechanistic rationale (based on nonclinical data), or evidence of nonclinical activity,
breakthrough therapy designation requires preliminary clinical evidence of a treatment effect that
may represent substantial improvement over available therapies for the treatment of a serious
condition. For purposes of breakthrough therapy designation, preliminary clinical evidence
means evidence that is sufficient to indicate that the drug may demonstrate substantial
improvement in effectiveness or safety over available therapies, but in most cases is not
sufficient to establish safety and effectiveness for purposes of approval. FDA expects that such
evidence generally would be derived from phase 1 or 2 trials. Nonclinical information could
support the clinical evidence of drug activity. In all cases, preliminary clinical evidence
demonstrating that the drug may represent a substantial improvement over available therapy
should involve a sufficient number of patients to be considered credible. However, FDA
recognizes that the data cannot be expected to be definitive at the time of designation.
Ideally, preliminary clinical evidence indicating a substantial improvement over available
therapies would be derived from a study that compares the investigational drug to an available
therapy (or placebo, if there is no available therapy) in clinical testing or from a study that
compares the new treatment plus SOC to the SOC alone. FDA encourages sponsors to obtain
some preliminary comparative data of this type early in development. Other types of clinical
data that also could be persuasive include single-arm studies comparing the new treatment with
well-documented historical experience. Generally, FDA expects that such historically controlled
data would be persuasive only if there is a large difference between the new treatment and
historical experience. For example, where lung function decline is a major manifestation of a
disease, single-arm study data showing that a new drug significantly increases lung function
could be persuasive if there is no available therapy that increases lung function. Data
demonstrating that a cancer drug substantially increases overall response rate compared with
historical controls (e.g., historical response rate with available therapy), with consideration of
duration of the response, also could be persuasive. Sponsors contemplating the use of historical
controls should consult FDA’s ICH guidance for industry E10 Choice of Control Group and
Related Issues in Clinical Trials for more-detailed discussions. 12
4.

May Demonstrate Substantial Improvement on Clinically Significant Endpoint(s)

We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA
Drugs guidance Web page at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm and the Biologics
guidance Web page at
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
11

Contains Nonbinding Recommendations
To support a breakthrough therapy designation, the preliminary clinical evidence must show that
the drug may demonstrate substantial improvement over available therapy on one or more
clinically significant endpoints.
Substantial Improvement: The determination of whether the improvement over available therapy
is substantial is a matter of judgment and depends on both the magnitude of the drug’s effect on a
clinically significant endpoint (which could include duration of the effect) and the importance of
the observed effect to the treatment of the serious condition or serious aspect of the condition. In
general, the preliminary clinical evidence should show a clear advantage over available therapy.
Approaches to demonstrating substantial improvement include the following:
x

Direct comparison of the new drug to available therapy shows a much greater or more
important response (e.g., complete responses where the control treatment generally
results only in partial responses). Such a trial could be conducted in treatment-naïve
patients or in those whose disease failed to respond to available therapies, either as a
comparison with the failed therapy (if ethically acceptable) or as a no-treatment
controlled study.

If there is no available therapy, the new drug shows a substantial and clinically
meaningful effect on an important outcome when compared with a placebo or a welldocumented historical control.

The new drug added to available therapy results in a much greater or more important
response compared to available therapy in a controlled study or to a well-documented
historical control. This trial also could be conducted in treatment-naïve patients or in
those whose disease failed to respond to available therapies.

The new drug has a substantial and clinically meaningful effect on the underlying cause
of the disease, in contrast to available therapies that treat only symptoms of the disease,
and preliminary clinical evidence indicates that the drug is likely to have a diseasemodifying effect in the long term (e.g., a sustained clinical benefit compared with a
temporary clinical benefit provided by available therapies).

The new drug reverses or inhibits disease progression, in contrast to available therapies
that only provide symptomatic improvement.

The new drug has an important safety advantage that relates to serious adverse reactions
(e.g., those that may result in treatment interruption) compared with available therapies
and has similar efficacy.

Clinically Significant Endpoint: For purposes of breakthrough therapy designation, FDA
considers clinically significant endpoint generally to refer to an endpoint that measures an effect
on irreversible morbidity or mortality (IMM) or on symptoms that represent serious
consequences of the disease. It can also refer to findings that suggest an effect on IMM or
serious symptoms, including:
12

Contains Nonbinding Recommendations

An effect on an established surrogate endpoint that typically would be used to support
traditional approval

An effect on a surrogate endpoint or intermediate clinical endpoint (see section VII.B.2.)
considered reasonably likely to predict a clinical benefit (i.e., the accelerated approval
standard)

A significantly improved safety profile compared with available therapy (e.g., less doselimiting toxicity for an oncology agent), with evidence of similar efficacy

In a breakthrough therapy designation request, a sponsor should provide justification for why the
endpoint or other findings should be considered clinically significant.
In rare cases, a pharmacodynamic (PD) biomarker may be considered a clinically significant
endpoint if it strongly suggests the potential for a clinically meaningful effect on the underlying
disease. In such cases, a sponsor should provide evidence supporting the use of the PD
biomarker. Such evidence should include, for example, (1) the extent of understanding of the
disease pathophysiology, (2) whether the biomarker is on a causal pathway of the disease
process, and (3) the time course of the drug’s effect on the biomarker (e.g., the biomarker can be
measured earlier than a surrogate endpoint used for accelerated approval). In addition, strong
evidence of the drug’s effect on the PD biomarker generally is expected. FDA is more likely to
rely on a PD biomarker for breakthrough therapy designation in a disease setting in which there
is no available therapy, if the evidence supports such use.
B.

Features of Breakthrough Therapy Designation

Intensive Guidance on an Efficient Drug Development Program, Beginning as
Early as Phase 1

As discussed previously, breakthrough therapy designation will usually mean that the effect of
the drug will be large compared with available therapies. In such cases, the development
program for the breakthrough therapy could be considerably shorter than for other drugs
intended to treat the disease being studied. However, FDA notes that a compressed drug
development program still must generate adequate data to demonstrate that the drug is safe and
effective to meet the statutory standard for approval. 13 Omitting components of the drug
development program that are necessary for such a determination can significantly delay, or even
preclude, marketing approval.
Sponsors can design efficient clinical trials in a number of ways. FDA will seek to ensure that a
sponsor of a product designated as a breakthrough therapy receives timely advice and interactive
communications to help the sponsor design and conduct a drug development program as

Section 505(d) of the FD&C Act and section 351(a) of the Public Health Service Act.
13

Contains Nonbinding Recommendations
efficiently as possible. 14 During these interactions, the Agency may suggest, or a sponsor may
propose, alternative clinical trial designs (e.g., adaptive designs, an enrichment strategy,
crossover or N-of-1 design, use of historical controls) or use of an interim analysis by a data
monitoring committee. 15 These trial designs may result in smaller trials or more efficient trials
that require less time to complete and may help minimize the number of patients exposed to a
potentially less efficacious treatment (i.e., the control group treated with available therapy).
Such approaches may be especially useful in studies in rare diseases. For example, single-arm
trials may be an important option in rare diseases with well-understood pathophysiology and a
well-defined disease course.
FDA anticipates that the review team and the sponsor will meet and interact throughout drug
development to address these and other important issues at different phases of development. In
addition, a sponsor should be prepared for a more rapid pace for other aspects of the drug
development (e.g., manufacturing (see section IX.A.), development of a necessary companion
diagnostic (see section IX.D.)).
2.

Organizational Commitment Involving Senior Managers

FDA intends to expedite the development and review of a breakthrough therapy by intensively
involving senior managers and experienced review and regulatory health project management
staff in a proactive, collaborative, cross-disciplinary review. Where appropriate, FDA also
intends to assign a cross-disciplinary project lead for the review team to facilitate an efficient
review of the drug development program. The cross-disciplinary project lead will serve as a
scientific liaison between members of the review team (e.g., medical; clinical pharmacology;
pharmacology-toxicology; chemistry, manufacturing, and controls (CMC); compliance;
biostatistics), facilitating coordinated internal interactions and communications with a sponsor
through the review division’s regulatory health project manager.
3.

Submission of Portions of an Application (Rolling Review)

FDA has determined that it is appropriate for a drug designated as a breakthrough therapy to be
able to obtain rolling review. Therefore, if FDA determines, after preliminary evaluation of
clinical data submitted by the sponsor, that a breakthrough therapy product may be effective, the
Agency may consider reviewing portions of a marketing application before the sponsor submits
the complete application (see Appendix 2).
4.

Other Actions to Expedite Review

As noted in IX. GENERAL CONSIDERATIONS, it is important that sponsors respond promptly to FDA
inquiries, which may include, for example, requests for information on various aspects of the drug development
program.
15
For more discussion of alternative clinical trial designs, see the draft guidance for industry Adaptive Design
Clinical Trials for Drugs and Biologics and the draft guidance for industry Enrichment Strategies for Clinical Trials
to Support Approval of Human Drugs and Biological Products. When final, these guidances will represent FDA’s
current thinking on these topics. See also the ICH E10 and the guidance for clinical trial sponsors Establishment
and Operation of Clinical Trial Data Monitoring Committees.
14

Contains Nonbinding Recommendations
In addition, such a product could be eligible for priority review if supported by clinical data at
the time of BLA, NDA, or efficacy supplement submission.
VII.

ACCELERATED APPROVAL

The accelerated approval provisions of FDASIA in section 506(c) of the FD&C Act provide that
FDA may grant accelerated approval to:
. . . a product for a serious or life-threatening disease or condition . . . upon a
determination that the product has an effect on a surrogate endpoint that is reasonably
likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier
than irreversible morbidity or mortality, that is reasonably likely to predict an effect on
irreversible morbidity or mortality or other clinical benefit, taking into account the
severity, rarity, or prevalence of the condition and the availability or lack of alternative
treatments.
For drugs granted accelerated approval, postmarketing confirmatory trials have been required to
verify and describe the anticipated effect on IMM or other clinical benefit (see sections VII.D.2.
and VII.D.3.). 16
This section describes the qualifying criteria, relevant terms, and the conditions of accelerated
approval. The provisions of FDASIA facilitate somewhat broader use of accelerated approval to
expedite patients’ access to important treatments for serious conditions. FDA believes the new
provisions provide additional flexibility concerning the implications of available therapy on
eligibility for accelerated approval (see section VII.A.2.). They also provide clarification
concerning the use of clinical endpoints (herein referred to as intermediate clinical endpoints) as
a basis for accelerated approval (see section VII.B.2.). In addition, the new provisions make
clear that FDA has the authority to consider pharmacologic or other evidence developed using
biomarkers or other scientific methods or tools, in conjunction with other data, in determining
whether an endpoint is reasonably likely to predict clinical benefit (see section VII.C.). 17 By
indicating that FDA should take into account, “. . . the severity, rarity, or prevalence of the
condition . . .” in considering whether to grant accelerated approval, FDASIA reinforces the
Agency’s longstanding commitment to regulatory flexibility regarding the evidence required to
support product approval for the treatment of serious or life-threatening diseases with limited
therapeutic options.
The accelerated approval pathway has been used primarily in settings in which the disease course
is long and an extended period of time would be required to measure the intended clinical benefit
of a drug. For example, accelerated approval has been used extensively in the approval of drugs
to treat a variety of cancers and human immunodeficiency virus (HIV) disease where an effect
16

Section 506(c)(2)(A) of the FD&C Act.
Section 506(c)(1)(B) of the FD&C Act. 21 CFR 314.510 and 601.41 provide that the Agency may consider “. . .
epidemiologic, therapeutic, pathophysiologic, or other evidence . . .” in determining whether an endpoint is
reasonably likely to predict clinical benefit. FDASIA provides that FDA may consider “. . . epidemiological,
pathophysiological, therapeutic, pharmacologic, or other evidence developed using biomarkers, for example, or
other scientific methods or tools.”
17

Contains Nonbinding Recommendations
on tumor growth or viral load can be assessed rapidly, but demonstrating an effect on survival or
morbidity generally requires lengthy and sometimes large trials because of the duration of the
typical disease course. Accelerated approval is also potentially useful in acute disease settings
where the intended clinical benefit can be demonstrated only in a very large study because the
clinical event that would need to be evaluated to demonstrate clinical benefit occurs rarely. For
example, accelerated approval could be used for an acute condition where an effect on a
surrogate endpoint could be shown in a small number of patients, but a much larger study would
be needed to show the effect on a clinical outcome, such as survival.
FDA encourages sponsors to communicate with the Agency early in development concerning the
potential eligibility of a drug for accelerated approval, proposed surrogate endpoints or
intermediate clinical endpoints, clinical trial designs, and planning and conduct of confirmatory
trials. A sponsor seeking accelerated approval may also need to prepare for a more rapid pace
for other aspects of the drug development (e.g., manufacturing (see section IX.A.), development
of a necessary companion diagnostic (see section IX.D.)).
A.

Qualifying Criteria for Accelerated Approval

At the time a product is granted accelerated approval, FDA has determined that an effect on the
endpoint used to support approval––a surrogate endpoint or an intermediate clinical endpoint––is
reasonably likely to predict clinical benefit. The principal risk of this approach is the possibility
that patients will be exposed to a drug that ultimately will not be shown to provide an actual
clinical benefit. In addition, there generally will be fewer, smaller, or shorter clinical trials than
is typical for a drug receiving traditional approval, which may generally mean there is less
information about the occurrence of rare or delayed adverse events. Uncertainty about whether
clinical benefit will be verified and the possibility of undiscovered risks are the primary reasons
that accelerated approval is reserved for drugs intended to treat a serious condition and that
appear to provide a meaningful advantage over available therapy.
1.

Serious Condition

See section III.A.
2.

Meaningful Advantage Over Available Therapy

The accelerated approval regulations state that accelerated approval is available only for drugs
that provide a meaningful therapeutic benefit over existing treatments. 18 The accelerated
approval provisions of section 901 of FDASIA (amending section 506 of the FD&C Act) require
FDA to “. . .tak[e] into account . . . the availability or lack of alternative treatments.”
Amended section 506(c) clarifies the Agency’s flexibility in administering the accelerated
approval program. For example, an alternative therapy with efficacy comparable to available
therapy, but with a different mechanism of action, could be of added clinical value in a disease
setting in which a significant number of patients may respond differently to the new therapy.
The discussion of unmet medical need in section III.C.2. provides examples of situations in
18

21 CFR 314.500 and 601.40.
16

Contains Nonbinding Recommendations
which a drug could be shown to provide a meaningful advantage over available therapy,
including some in which there may not be a demonstrated direct efficacy or safety advantage.
Section III.B. describes what constitutes available therapy when determining whether a drug
provides a meaningful advantage.
3.

Demonstrates an Effect on an Endpoint That Is Reasonably Likely to Predict
Clinical Benefit

These endpoints are discussed in section VII.B. The basis for determining whether an endpoint
is reasonably likely to predict clinical benefit is discussed in section VII.C.
B.

Accelerated Approval Endpoints

The two types of endpoints that can be used as a basis for accelerated approval are: (1) a
surrogate endpoint that is considered reasonably likely to predict clinical benefit and (2) a
clinical endpoint that can be measured earlier than IMM that is reasonably likely to predict an
effect on IMM or other clinical benefit (also see section VII.D.2.). For purposes of this
guidance, these categories of endpoints are referred to as surrogate endpoints and intermediate
clinical endpoints, respectively.
A clinical endpoint is a characteristic or variable that directly measures a therapeutic effect of a
drug––an effect on how a patient feels (e.g., symptom relief), functions (e.g., improved
mobility), or survives.
A clinical benefit is a positive therapeutic effect that is clinically meaningful in the context of a
given disease. The clinical benefit must be weighed against a treatment’s risks to determine
whether there is an overall benefit for patients (i.e., a positive benefit-risk profile).
1.

Surrogate Endpoints

For purposes of accelerated approval, a surrogate endpoint is a marker, such as a laboratory
measurement, radiographic image, physical sign, or other measure, that is thought to predict
clinical benefit, but is not itself a measure of clinical benefit. Depending on the strength of the
evidence supporting the ability of a marker to predict clinical benefit, the marker may be a
surrogate endpoint that is known to predict clinical benefit (a validated surrogate endpoint that
could be used for traditional approval), a surrogate endpoint that is reasonably likely to predict a
drug’s intended clinical benefit (and that could therefore be used as a basis for accelerated
approval), or a marker for which there is insufficient evidence to support reliance on the marker
as either kind of surrogate endpoint (and that therefore cannot be used to support traditional or
accelerated approval of a marketing application).
Examples of surrogate endpoints that FDA has used to support accelerated approval include the
following:
x

Prolonged suppression of HIV viral load in plasma has been shown to reduce the
morbidity and mortality associated with HIV disease and has been the basis for
17

Contains Nonbinding Recommendations
traditional approval. Shorter-term suppression of viral load has been used in the past as a
surrogate to support accelerated approval because it was considered reasonably likely to
predict an effect on morbidity or mortality. Data now demonstrate that short-term
suppression of viral load may support full approval, in some circumstances. 19
x

Clearance of bacteria from the blood stream as evidenced by a laboratory measurement of
bacteria in the blood has been considered reasonably likely to predict the clinical
resolution of infection.

Outcomes of 6-month follow-up treatment (i.e., sputum culture status and infection
relapse rate) have been considered reasonably likely to predict the resolution of
pulmonary tuberculosis.

Decrease in iron stores for patients with iron overload caused by thalassemia has been
considered reasonably likely to predict a decrease in transfusion-related adverse events
caused by iron overload in the body.

Radiographic evidence of tumor shrinkage (response rate) in certain cancer types has
been considered reasonably likely to predict an improvement in overall survival.
2.

Intermediate Clinical Endpoints

For purposes of accelerated approval, an intermediate clinical endpoint is a measurement of a
therapeutic effect that can be measured earlier than an effect on IMM and is considered
reasonably likely to predict the drug’s effect on IMM or other clinical benefit. An important
question is whether the demonstrated therapeutic effect alone would be a basis for traditional
approval. Approvals for products for serious conditions based on clinical endpoints other than
IMM will usually be considered under traditional approval procedures. Approvals based on such
clinical endpoints will be considered under the accelerated approval pathway only when it is
essential to determine effects on IMM or other clinical benefit in order to confirm the predicted
clinical benefit that led to approval. Although FDA has limited experience with accelerated
approvals based on intermediate clinical endpoints, FDA believes intermediate clinical endpoints
generally could be used to support accelerated approval in situations such as:
x

A study demonstrates a relatively short-term clinical benefit in a chronic disease setting
in which assessing durability of the clinical benefit is essential for traditional approval,
but the short-term benefit is considered reasonably likely to predict long-term benefit.

A clinical endpoint demonstrates a clinical benefit that is reasonably likely to predict an
effect on IMM in a disease setting in which it is essential to confirm the effect on IMM
(e.g., because available therapy has established effects on IMM).

See the draft guidance for industry Human Immunodeficiency Virus-1 Infection: Developing Antiretroviral Drugs
for Treatment. When final, this guidance will represent FDA's current thinking on this topic.
18

Contains Nonbinding Recommendations
Examples of cases in which FDA has used an intermediate clinical endpoint to support
accelerated approval include the following:
x

A treatment for multiple sclerosis was approved based on a large therapeutic effect on
relapse rate through approximately 13 months of treatment, but where there was
uncertainty about the durability of the observed effect. Under accelerated approval, the
sponsor was required to continue the existing trials into the postmarketing period to
confirm durability of the observed effect at 2 years.

A treatment for preterm labor was approved based on a demonstration of delay in
delivery. Under accelerated approval, the sponsor was required to conduct postmarketing
studies to demonstrate improved long-term postnatal outcomes.

FDA will not grant accelerated approval to products that meet standards for traditional approval.
Sponsors considering a development program for accelerated approval based on an intermediate
clinical endpoint should discuss their development program with the appropriate review division
early in drug development.
C.

Evidentiary Criteria for Accelerated Approval

Drugs granted accelerated approval must meet the same statutory standards for safety and
effectiveness as those granted traditional approval. 20 For effectiveness, the standard is
substantial evidence based on adequate and well-controlled clinical investigations. 21 For safety,
the standard is having sufficient information to determine whether the drug is safe for use under
conditions prescribed, recommended, or suggested in the proposed labeling. 22 Under accelerated
approval, FDA can rely on a particular kind of evidence, such as a drug’s effect on a surrogate
endpoint, as a basis for approval. FDA carefully evaluates such evidence to ensure that any
remaining doubts about the relationship of the effect on the surrogate to clinical benefit are
resolved by additional postapproval studies or trials. 23 An application for accelerated approval
should also include evidence that a proposed surrogate endpoint or an intermediate clinical
endpoint is reasonably likely to predict the intended clinical benefit of a drug.
Determining whether an endpoint is reasonably likely to predict clinical benefit is a matter of
judgment that will depend on the biological plausibility of the relationship between the disease,
the endpoint, and the desired effect and the empirical evidence to support that relationship. The
empirical evidence may include “. . . epidemiological, pathophysiological, therapeutic,
pharmacologic, or other evidence developed using biomarkers, for example, or other scientific
methods or tools.” 24 Evidence of pharmacologic activity alone is not sufficient, however. 25
Clinical data should be provided to support a conclusion that a relationship of an effect on the

Section 505(d) of the FD&C Act.
Section 505(d)(5) of the FD&C Act.
22
Section 505(d)(1) of the FD&C Act.
23
57 FR 58942 at 58948.
24
Section 506(c)(1)(B) of the FD&C Act.
25
57 FR 58942.
21

Contains Nonbinding Recommendations
surrogate endpoint or intermediate clinical endpoint to an effect on the clinical outcome is
reasonably likely.
In making the judgment as to whether a drug’s effect on a given endpoint is reasonably likely to
predict clinical benefit, FDA considers all relevant evidence and may consult external experts, as
needed. This guidance provides an overview of some of the important factors to consider in
identifying and assessing the predictive potential of surrogate endpoints or intermediate clinical
endpoints. This guidance does not, however, address the specific clinical evidence needed to
support a conclusion that a particular surrogate endpoint or intermediate clinical endpoint is
reasonably likely to predict clinical benefit or IMM because such evidence is case-specific and is
not readily generalizable.
1.

Understanding of the Disease Process

Surrogate endpoints are often thought to be a measure of the following, for example:
x

The underlying cause of the disease (e.g., elevated uric acid and gout, elevated blood
pressure and hypertensive cardiovascular disease, low thyroxine levels and
hypothyroidism, high ammonia levels and urea cycle disorders)

An effect that predicts the ultimate outcome (e.g., tumor shrinkage could be expected to
delay symptomatic progression and improve survival, diuresis could be expected to
improve symptoms of heart failure, effects on serum creatinine or glomerular filtration
rate (if not transient or reversible) are accepted surrogates for predicting effects on
chronic renal disease and delaying the occurrence of end-stage renal disease)

The state of the pathophysiologic pathway leading to the clinical outcome (e.g., low
levels of the biomarker that increase with replacement of a missing enzyme or clotting
factor)

In such cases, the extent to which the pathophysiology of a disease is understood is an important
factor in determining whether an endpoint is reasonably likely to predict clinical benefit. If the
disease process is complex, has multiple pathophysiologic or causal pathways, and is poorly
understood, it may be difficult to determine whether an effect on a surrogate endpoint represents
a meaningful effect on the causal pathway. For example, for some reasonably well-understood
enzyme deficiencies, replacement of the deficient enzyme reliably predicts clinical benefit. In
contrast, other enzyme deficiencies may involve a defect for which the pathophysiologic or
causal pathways are not well understood and where enzyme replacement as measured by blood
levels, but not tissue levels, will not reasonably predict the disease course or treatment results.
Some effects on well-established, disease-related biomarkers 26 may have little or no ability to
predict clinical benefit or their ability to predict benefit may vary depending on the disease or the

FDA's CDER has established the Biomarker Qualification Program to support work with external scientists and
clinicians in developing biomarkers. The Biomarker Qualification Program offers a formal process to guide
submitters as they develop biomarkers and rigorously evaluate them for use in the regulatory process. Details on the
20

Contains Nonbinding Recommendations
intervention. For example, in a patient with a fever caused by an infectious disease, a fall in a
patient’s body temperature in response to a non-steroidal anti-inflammatory drug does not predict
the drug’s effect on the disease. However, a fall in a patient’s body temperature in response to
an antibiotic may be an indication of an effect on the disease. Similarly, in prostate cancer,
increased levels of prostate-specific antigen (PSA) may be the result of advancing tumor burden.
Therefore, PSA may be correlated with the progression of prostate cancer and the risks of
mortality. However, the relationship between increasing PSA and disease progression and
morbidity is not uniform. Thus the ability of a drug to lower PSA levels cannot necessarily be
relied upon to predict the drug’s clinical benefit.
2.

Understanding of the Relationship Between the Drug’s Effect and the Disease
Process

The extent to which a drug’s effect on the surrogate endpoint is known to predict an effect on the
disease either because the effect is on the causal pathway or correlates with clinical outcomes is
critical. Sometimes this relationship can be assessed epidemiologically but it is most
persuasively established by knowing that a drug that affects the surrogate endpoint also affects a
clinical outcome. Thus, lowering blood pressure has been shown repeatedly, with a wide variety
of drugs, to reduce the incidence of stroke and cardiovascular disease in people with
hypertension. Similarly, killing infecting bacteria or viruses leads to curing infectious disease
and shrinking a tumor for a sustained period can lead to improved survival in patients with some
cancers. These surrogate endpoint responses are thus understood to have positive effects on the
disease process.
Examples of factors to consider in identifying and assessing a surrogate endpoint thus include the
following:
x

Whether there is reliable and consistent epidemiologic evidence supporting the
relationship between the endpoint and the intended clinical benefit. 27

How precisely the epidemiologic relationship between the endpoint and clinical outcome
is defined. For example, the extent to which an abnormal endpoint corresponds to a
worse clinical outcome, as is the case for blood pressure and low-density lipoprotein
(LDL) cholesterol. (The stronger the correlation between the abnormality and clinical
outcome, the stronger the basis for concluding that an effect on the endpoint would have
a reasonably well-defined effect on the clinical outcome.)

Whether the effect on the surrogate endpoint has been shown to predict a clinical benefit
with another drug or drugs. This factor would generally be more persuasive if the drug is
in the same or a closely related pharmacological class.

program are available at
http://www.fda.gov/drugs/developmentapprovalprocess/drugdevelopmenttoolsqualificationprogram/
ucm284076.htm.
27
Note, however, that such a relationship does not always predict a favorable effect, as illustrated by failure of drugs
that effectively lower premature ventricular beat rates or raise high-density lipoprotein (HDL) cholesterol to have
the expected cardiovascular benefits.
21

Contains Nonbinding Recommendations

Particularly in rare diseases, there may be limited information in the literature, lack of in-depth
epidemiological or historical data, and little or no experience with other drugs to inform the
interpretation of surrogate endpoints or intermediate clinical endpoints. FDA may consult with
external experts on surrogate endpoints and intermediate clinical endpoints where there is a lack
of historical data for a given disease. 28
D.

Conditions of Accelerated Approval

Promotional Materials

Unless otherwise informed by the Agency, an applicant must submit to the Agency for
consideration during the preapproval review period copies of all promotional materials, including
promotional labeling as well as advertisements, intended for dissemination or publication within
120 days following marketing approval. 29 After 120 days following marketing approval, unless
otherwise informed by the Agency, the applicant must submit promotional materials at least 30
days prior to the intended time of initial dissemination of the labeling or initial publication of the
advertisement. 30
2.

Confirmatory Trials

For drugs granted accelerated approval, postmarketing confirmatory trials have been required to
verify and describe the anticipated effect on IMM or other clinical benefit. These trials must be
completed with due diligence. 31
FDA has interpreted the due diligence requirement to mean that the postmarketing trial(s)
intended to verify the clinical benefit must be conducted promptly to facilitate determination, as
soon as possible, of whether clinical benefit has been verified. The protocol for a postmarketing
trial should be developed as early as possible, and timelines for the trial should be specified; for
example, timelines for enrollment and trial completion should be stipulated. There should be
agreement between FDA and the sponsor on the design and conduct of the confirmatory trial(s).
If it is clear during development that a product is intended to be approved under accelerated
approval on the basis of a surrogate endpoint or an intermediate clinical endpoint, confirmatory
trial(s) should be underway at the time the marketing application is submitted. If it is not clear
until shortly before or after submission of a marketing application that a surrogate endpoint or an
intermediate clinical endpoint will be the proposed basis for accelerated approval, there should
be agreement on the design and conduct of such trial(s) before approval.

See, for example, section 569(a)(2), (b), and (c) of the FD&C Act, Consultation With External Experts on Rare
Diseases, Targeted Therapies and Genetic Targeting of Treatments, which describes general consideration for
consultation with external experts, topics for consultation, and classification as special Government employees.
29
21 CFR 314.550 and 601.45.
30
21 CFR 314.550 and 601.45.
31
Section 506(c)(3)(A) of the FD&C Act and §§ 314.510 and 601.41. Where confirmatory trials verify clinical
benefit, FDA generally will terminate the requirement (21 CFR 312.560 and 601.46).
22

Contains Nonbinding Recommendations
Generally, the confirmatory trial would evaluate a clinical endpoint that directly measures
clinical benefit. For example, the confirmatory trial population would ordinarily be the same
disease population that was studied to support accelerated approval. In some cases, however, the
commercial availability of a drug following accelerated approval may make it difficult to enroll
patients in the same disease population. In these cases, a confirmatory trial may be conducted in
a different but related population that is capable of verifying the predicted clinical benefit. This
is often the case in oncology, where after accelerated approval of a drug for late-stage disease is
granted, the confirmatory trial is conducted in an earlier stage of the same cancer.
There are also cases in which additional evaluation (longer duration) of the same surrogate
endpoint that was used to support accelerated approval (rather than a clinical endpoint) in the
same population could be persuasive evidence of clinical benefit. For example, in the case of
HIV treatment, an effect on viral load of relatively short duration (24 weeks) was considered
reasonably likely to predict clinical benefit supporting accelerated approval. An effect of longer
(1 year) viral load suppression was more convincingly related to durable clinical benefit in the
setting of lifelong therapy and thus was used to verify clinical benefit for traditional approval.32
When it is possible to use a later effect in a trial to verify the effect seen earlier in the same trial
that supported accelerated approval, the same clinical trial(s) can be used to support accelerated
approval and verify and describe the clinical benefit. In this case, the protocol and the statistical
analysis plan should clearly account for an analysis of the surrogate endpoint data to provide
support for accelerated approval, with continuation of the randomized trial(s) to obtain data on
the clinical endpoint that will be the basis for verifying the clinical benefit. When the same trial
is used to support accelerated approval and verify clinical benefit, the data to verify the clinical
benefit may be, in some cases, nearly complete by the time of accelerated approval.
3.

Withdrawal of Accelerated Approval

FDA may withdraw approval of a drug or indication approved under the accelerated approval
pathway if, 33 for example:
x

A trial required to verify the predicted clinical benefit of the product fails to verify such
benefit.

Other evidence demonstrates that the product is not shown to be safe or effective under
the conditions of use.

The applicant fails to conduct any required postapproval trial of the drug with due
diligence.

Although an effect on viral load changes of short duration had been used in the past as a surrogate endpoint to
support accelerated approval, FDA now considers this endpoint acceptable, in some circumstances, to grant
traditional approval based on years of experience with this endpoint.
33
See section 506(c)(3) of the FD&C Act and §§ 314.530(a) and 601.43(a). Part 314, subpart E and part 601,
subpart H describe additional grounds for withdrawal.
23

Contains Nonbinding Recommendations
x

The applicant disseminates false or misleading promotional materials relating to the
product.

Approval of a drug may be withdrawn if trials fail to verify clinical benefit or do not demonstrate
sufficient clinical benefit to justify the risks associated with the drug (e.g., show a significantly
smaller magnitude or duration of benefit than was anticipated based on the observed effect on the
surrogate).
If FDA determines there are grounds for withdrawal, the Agency may ask the applicant to
request withdrawal of approval under § 314.150(d) or notify the applicant of FDA’s proposal to
withdraw approval in a notice of opportunity for hearing (NOOH). The NOOH generally will
state the proposed grounds for withdrawal of approval. 34 Upon receipt of an NOOH, an
applicant has 15 days to file a written request for a hearing. If an applicant does not request a
hearing within 15 days, the applicant waives its opportunity for hearing. 35 An applicant may
also request the Agency to withdraw approval of an application approved under accelerated
approval. 36
VIII. PRIORITY REVIEW DESIGNATION
An application for a drug will receive priority review designation if it is for a drug that treats a
serious condition and, if approved, would provide a significant improvement in safety or
effectiveness. In addition, specific statutory provisions provide for priority review for various
types of applications, described in section IV. A priority designation is intended to direct overall
attention and resources to the evaluation of such applications. This section describes the
qualifying criteria and the features of priority review designation. Appendix 1 describes the
process for priority review designation.
A.

Qualifying Criteria for Priority Review Designation

Serious Condition

See section III.A.
2.

Demonstrating the Potential To Be a Significant Improvement in Safety or
Effectiveness

On a case-by-case basis, FDA determines at the time of NDA, BLA, or efficacy supplement
filing whether the proposed drug would be a significant improvement in the safety or
effectiveness of the treatment, prevention, or diagnosis of a serious condition. Significant
improvement may be illustrated by the following examples:
x

Evidence of increased effectiveness in treatment, prevention, or diagnosis of a condition

21 CFR 314.530(b) and 601.43(b).
21 CFR 314.530(c)(1) and 601.43(c)(1).
36
21 CFR 314.150(c) and 601.5(a).
35

Contains Nonbinding Recommendations
x

Elimination or substantial reduction of a treatment-limiting adverse reaction

Documented enhancement of patient compliance that is expected to lead to an
improvement in serious outcomes

Evidence of safety and effectiveness in a new subpopulation

Although such evidence can come from clinical trials comparing a marketed product with the
investigational drug, a priority review designation can be based on other scientifically valid
information. Generally, if there is an available therapy (see section III.B.), sponsors should
compare their investigational drug to the available therapy in clinical testing with an attempt to
show superiority relating to either safety or effectiveness. Alternatively, sponsors could show
the drug’s ability to effectively treat patients who are unable to tolerate, or whose disease failed
to respond to, available therapy or show that the drug can be used effectively with other critical
agents that cannot be combined with available therapy. Although such showings would usually
be based on randomized trials, other types of controls could also be persuasive, for example,
historical controls. 37
B.

Features of Priority Review Designation

A priority review designation means FDA’s goal is to take action on the marketing application
within 6 months of receipt (compared with 10 months under standard review). The PDUFA
review clock for applications filed by FDA under the Program is described in section IV.
IX.

GENERAL CONSIDERATIONS

Communication with the Agency is a critical aspect of expedited programs. FDA will strive to
provide a timely response to a sponsor’s inquiry regarding an expedited development program.
It is equally critical that a sponsor respond promptly to FDA’s inquiries. 38 This applies to formal
meetings and related inquiries, written correspondence, and other interactions. In addition to the
many types of formal meetings 39 and correspondence the Agency offers to sponsors, additional
considerations for sponsors of expedited programs are highlighted in this section.
A.

Manufacturing and Product Quality Considerations

The sponsor of a product that receives an expedited drug development designation may need to
pursue a more rapid manufacturing development program to accommodate the accelerated pace
of the clinical program. The sponsor’s product quality and CMC teams should initiate early

Sponsors contemplating the use of historical controls should consult ICH E10 for more-detailed discussions.
For example, FDA may request updates on a breakthrough therapy designation program in order to provide the
sponsor with guidance on drug development.
39
See the guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants.
Also see the CDER 21st Century Review Process Desk Reference Guide accessible at
http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ManualofPoliciesProcedures/UCM218757.htm.
38

Contains Nonbinding Recommendations
communication with FDA to ensure that the manufacturing development programs and timing of
submissions meet the Agency’s expectations for licensure or marketing approval. 40
When sponsors receive an expedited drug development designation, they should be prepared to
propose a commercial manufacturing program that will ensure availability of quality product at
the time of approval. The proposal should consider estimated market demand and the
commercial manufacturing development plan. The proposal should also consider manufacturing
facilities and a lifecycle approach to process validation. Additionally, the proposal should
include a timeline for development of the manufacturing capabilities with goals aligned with the
clinical development program. After the initial discussion following designation, frequent
communication during development will generally facilitate meeting manufacturing development
goals and product quality goals.
Sponsors of such products should allow for an earlier submission of the CMC section (including
product quality information) for timely review, and, critically, for inspection activities. 41
Coordination with the sponsor and contract manufacturers may be necessary to ensure that
manufacturing facilities and equipment are ready for inspection during review of the clinical
section of the application. A comprehensive meeting with FDA’s product quality review groups
in advance of submission may facilitate the quality assessment of products designated for
expedited programs.
Although sponsors must ensure the availability of quality product at the time of approval, FDA
may exercise some flexibility on the type and extent of manufacturing information that is
expected at the time of submission and approval for certain components (e.g., stability updates,
validation strategies, inspection planning, manufacturing scale-up). The level of flexibility will
be determined on a case-by-case basis after consideration of factors such as the following: (1)
product characteristics, (2) seriousness of the condition and medical need, (3) manufacturing
processes, (4) the robustness of the sponsor’s quality system, and (5) the strength of the
sponsor’s risk-based quality assessment. FDA’s consideration of the sponsor’s proposal for an
integrated postmarketing plan will also take into account whether elements of the plan may be
appropriately executed as a postmarketing commitment or requirement. For example, FDA will
consider impacts on clinical performance, such as safety and immunogenicity. Sponsors should
meet with the Agency to discuss their proposed plan as soon as possible and no later than the
pre-NDA or pre-BLA meeting.
B.

Nonclinical Considerations

To ensure timely submission and review of nonclinical data, sponsors should initiate early
communication with FDA for their nonclinical study programs. Considerations such as study
40

See the guidance for industry IND Meetings for Human Drugs and Biologics Chemistry, Manufacturing, and
Controls Information.
41
For products designated as fast track or breakthrough therapy, this can be accomplished through rolling review
(see 2. Submission of Portions of an Application (Rolling Review), 3. Submission of Portions of an Application
(Rolling Review), and Appendix 2: Processes for Rolling review). For products submitted under an NDA without
such a designation, flexibility is permitted in § 314.50(d)(1)(iv). For BLAs without such a designation, there is
flexibility also to allow an early submission of the CMC section when resources permit.
26

Contains Nonbinding Recommendations
protocol modifications, sequence and scheduling of studies, and the need for specific studies
(e.g., long-term toxicity) may be important in the context of expedited drug development. FDA
will provide guidance to sponsors on the development of appropriate and timely nonclinical data
needed to support an application for marketing approval or licensure.
C.

Clinical Inspection Considerations

Sponsors should anticipate the Agency’s need to inspect clinical trials, including, if applicable,
the analytical component of bioavailability or bioequivalence studies. Sponsors should be
prepared for inspections to be scheduled by the Agency early in the application review process
so inspection results are available to inform the review division and to allow time for the sponsor
to address significant inspection findings. To select sites for clinical inspections, it is important
for reviewers to have timely access to adequate and accurate data in BLA, NDA, or supplement
submissions. Sponsors should initiate early communication with FDA about information
required for inspection planning and conduct.
D.

Companion Diagnostics

Development programs utilizing one or more of the expedited programs described in this
guidance may involve an in vitro companion diagnostic device. Sponsors using one of the
expedited programs for a product that involves an in vitro companion diagnostic device should
consult FDA’s guidance on the topic. 42
X.

PAPERWORK REDUCTION ACT OF 1995

This guidance contains information collection provisions that are subject to review by the Office
of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C.
3501-3520). The time required to complete this information collection is estimated to average
30 hours per response to prepare a priority review designation request and 70 hours per response
to prepare a breakthrough therapy designation request, including the time to review instructions,
search existing data sources, gather the data needed, and complete and review the information
collection. Send comments regarding this burden estimate or suggestions for reducing this
burden to:
Food and Drug Administration
Center for Drug Evaluation and Research
Office of Medical Policy
10903 New Hampshire Avenue, Bldg. 51, rm. 6360
Silver Spring, MD 20993-0002
This guidance also refers to previously approved collections of information found in FDA
regulations. The collections of information in 21 CFR 202.1, certain parts of part 314, part
601, and sections 506(b)(1), 735, and 736 of the FD&C Act have been approved under OMB
control numbers 0910-0686, 0910-0001, 0910-0338, and 0910-0297. An agency may not
conduct or sponsor, and a person is not required to respond to, a collection of information
42
See the it
draft
guidance
for industryvalid
and Food
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Drug Administration
staffOMB
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Companion
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unless
displays
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OMB
number. The
control
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Devices.
When
final,
this
guidance
will
represent
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current
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on
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information collection is 0910-0765. The current expiration date is available at
https://www.reginfo.gov (search ICR and enter27OMB control number).

Contains Nonbinding Recommendations
APPENDIX 1: PROCESSES FOR FAST TRACK, BREAKTHROUGH THERAPY, AND
PRIORITY REVIEW DESIGNATIONS
This appendix describes general processes applicable to the submission and review of fast track,
breakthrough therapy, and priority review designations.
A.

Process for Fast Track Designation

When to Send a Designation Submission

Sponsors may request fast track designation when the IND is first submitted or at any time
thereafter before receiving marketing approval of their BLA or NDA. The IND and potential
fast track designation may be discussed before an IND submission in a pre-IND meeting, but a
decision on designation would await submission of the IND. As a practical matter, FDA should
ordinarily receive a fast track designation request no later than the sponsor's pre-BLA or preNDA meeting with the Agency because many of the features of fast track designation will not
apply after that time. If a sponsor’s drug development program is granted fast track designation
for one indication and has subsequently obtained data to support fast track designation for
another indication, the sponsor should submit a separate request.
2.

Where to Send a Designation Submission

The IND or amendment should be sent to the IND administrative file to the attention of the
appropriate review division or office in CDER or CBER.
3.

Content of a Designation Submission

Fast track designation requests should contain the following information (in most cases, this
information could be captured in approximately 10 to 20 pages):
x

If the fast track designation request is submitted to the sponsor’s IND as an amendment,
identification of the submission in the cover letter as a REQUEST FOR FAST TRACK
DESIGNATION in bold, uppercase letters. If the request is submitted with an initial
IND, identification of the submission in the cover letter as both an INITIAL
INVESTIGATIONAL NEW DRUG SUBMISSION and REQUEST FOR FAST
TRACK DESIGNATION in bold, uppercase letters.

In the cover letter of the submission, the name of the sponsor’s contact person and the
contact person’s address, email address, telephone number, and fax number.

If applicable, the IND application number.

If available, for drug products, the proprietary name and active ingredient and for
biological products, the proper name and proprietary name.

The division or office to which the IND is being submitted or in which it is active.
28

Contains Nonbinding Recommendations
x

The proposed indication(s).

A concise summary of information that supports the fast track designation request for the
indication being studied, including the following:
o The basis for considering the drug to be one intended to treat a serious condition
o The basis for considering the drug to have the potential to address an unmet
medical need and an explanation of how this potential is being evaluated in the
planned drug development program (e.g., a description of the trials intended to
evaluate this potential)

If applicable, a list of documents previously submitted to the IND that is considered
relevant to the designation request, with reference to submission dates. Paper
submissions can be resubmitted to FDA as appendices to the designation request.
4.

FDA Response

FDA will respond to fast track designation requests within 60 calendar days of receipt of the
request.
a.

Designation letter

If the Agency determines that the criteria for designation as a fast track drug development
program have been met, the designation letter will:
x

State that fast track designation is granted for development of the product for use in
treating the specific serious condition

Point out that the sponsor should design and perform studies that can show whether the
product meets an unmet medical need

Alert the sponsor to the need for the drug development program to continue to meet the
criteria for fast track designation
b.

Nondesignation letter

If the Agency determines that a fast track designation request was incomplete or that the drug
development program failed to meet the criteria for fast track designation, the Agency will send a
nondesignation letter to the sponsor. The nondesignation letter will state that fast track
designation is not granted and explain the reasons for the Agency's decision.
5.

Continued Designation as a Fast Track Development Program

Over the course of drug development, it can be expected that some products granted fast track
designation will not continue to meet the criteria for fast track designation. A drug product in a
29

Contains Nonbinding Recommendations
fast track development program may not continue to meet the criteria if the drug: (1) no longer
demonstrates a potential to address unmet medical need or (2) is not being studied in a manner
that shows the drug product can treat a serious condition and meets an unmet medical need. The
drug product may no longer demonstrate a potential to address unmet medical need, for example,
if a new product was approved under a traditional approval that addressed the same need or if
emerging clinical data failed to show that the product in a fast track development program had
the anticipated advantage over available therapy. For products in fast track drug development
programs, the Agency expects that the appropriateness of considering particular drug
development plans as part of the fast track program will be discussed and evaluated during the
drug development process, including at the end-of-phase 2 meeting and the pre-BLA or preNDA meeting. If the sponsor recognizes that the fast track drug development program will no
longer be pursued, the sponsor should inform the Agency of this change.
When fast track designation is no longer supported by emerging data or the designated drug
development program is no longer being pursued, the Agency may choose to send a letter
notifying the sponsor that the program is no longer designated as a fast track drug development
program.
B.

Process for Breakthrough Therapy Designation

When to Send a Designation Submission

Although sponsors may request breakthrough therapy designation when the IND is first
submitted or at any time thereafter, they should not send breakthrough therapy designation
requests until they have preliminary clinical evidence indicating that “. . . the drug may
demonstrate substantial improvement over existing therapies on 1 or more clinically significant
endpoints.” 43 FDA therefore expects that in most cases breakthrough therapy designation
requests would be submitted as an amendment to the IND. Ideally, FDA should receive a
breakthrough therapy designation request before initiation of the clinical trial(s) intended to serve
as the primary basis for demonstration of efficacy if most of the benefits of designation are to be
obtained. Because the primary intent of breakthrough therapy designation is to develop evidence
needed to support approval as efficiently as possible, FDA anticipates that breakthrough therapy
designation requests will rarely be made after the submission of an original BLA or NDA or a
supplement. If a sponsor’s drug development program is granted breakthrough therapy
designation for one indication and has subsequently obtained preliminary clinical evidence to
support breakthrough therapy designation for another indication, the sponsor should submit a
separate request.
If a sponsor has not requested breakthrough therapy designation, FDA may suggest that the
sponsor consider submitting a request if: (1) after reviewing available data and information, the
Agency thinks the drug development program may meet the criteria for breakthrough therapy
designation and (2) the remaining drug development program and review can benefit from the
designation. However, the Agency still needs to review the submitted request (including
preliminary clinical evidence) to determine if it meets the criteria for breakthrough therapy
designation. A suggestion by the Agency that a sponsor consider submitting a request for
43

Section 506(a)(1) of the FD&C Act.
30

Contains Nonbinding Recommendations
breakthrough therapy designation is advisory and should not be interpreted as guaranteeing
breakthrough therapy designation once a request is submitted and reviewed.
2.

Where to Send a Designation Submission

The IND or amendment should be submitted to the IND administrative file to the attention of the
appropriate review division or office in CDER or CBER.
3.

Content of a Designation Submission

Breakthrough therapy designation requests should contain the following information (in most
cases, this information could be captured in approximately 10 to 20 pages):
x

If the breakthrough therapy designation request is submitted to the sponsor’s IND as an
amendment, identification of the submission in the cover letter as a REQUEST FOR
BREAKTHROUGH THERAPY DESIGNATION in bold, uppercase letters. If the
request is submitted with an initial IND, identification of the submission in the cover
letter as both an INITIAL INVESTIGATIONAL NEW DRUG SUBMISSION and
REQUEST FOR BREAKTHROUGH THERAPY DESIGNATION in bold,
uppercase letters.

In the cover letter of the submission, the name of the sponsor’s contact person and the
contact person’s address, email address, telephone number, and fax number.

If applicable, the IND application number.

If available, for drug products, the proprietary name and active ingredient and for
biological products, the proper name and proprietary name.

The division or office to which the IND is being submitted or in which it is active.

The proposed indication(s).

A concise summary of information that supports the breakthrough therapy designation
request for the indication being studied, including the following:
o The basis for considering the drug to be one intended to treat a serious condition
o The preliminary clinical evidence that the drug may demonstrate substantial
improvement over available therapies. 44 FDA does not expect the sponsor to
submit primary data (data sets); but, the sponsor should describe the preliminary
clinical evidence, including, for example, a brief description of available therapies
(if there are any) and their effectiveness; justification for the comparator selected

If the designation is being submitted with the IND, examples of information that could be submitted to support a
designation request include data from foreign clinical trials not conducted under IND, a different formulation or
route of administration, a use in an unrelated indication, or the published literature.
31

Contains Nonbinding Recommendations
for the clinical studies, the study design, the population studied, and the endpoint
used; and a brief description of the study results and statistical analyses
(including, for example, subgroup analysis).
x

FDA Response

FDA will respond to breakthrough therapy designation requests within 60 calendar days of
receipt of the request.
a.

Designation letter

If the Agency determines that the criteria for designation as a breakthrough therapy development
program have been met, the designation letter will:
x

State that breakthrough therapy designation is granted for development of the product for
use in treating the specific serious condition

Explain that FDA will work closely with the sponsor to provide guidance on subsequent
development, including providing advice on generating evidence needed to support the
drug approval in an efficient manner

Alert the sponsor to the need for the drug development program to continue to meet the
criteria for breakthrough therapy designation
b.

Nondesignation letter

If the Agency determines that a breakthrough therapy designation request was incomplete or that
the drug development program failed to meet the criteria for breakthrough therapy designation,
the Agency will send a nondesignation letter to the sponsor. The nondesignation letter will state
that a breakthrough therapy designation is not granted and explain the reasons for the Agency’s
decision. Where appropriate, the letter may also include advice to the sponsor regarding
subsequent development, including what would be needed in a new breakthrough therapy
designation request.
5.

Continued Designation as a Breakthrough Therapy Development Program

Over the course of drug development, it can be expected that some products granted
breakthrough therapy designation will no longer be considered a breakthrough therapy. For
example, a drug development program may be granted breakthrough therapy designation using
early clinical testing that shows a much higher response rate than available therapies. However,
subsequent interim data derived from a larger study may show a response that is substantially
smaller than the response seen in early clinical testing. Another example is where breakthrough
32

Contains Nonbinding Recommendations
therapy designation is granted to two drugs that are being developed for the same use. If one of
the two drugs gains traditional approval, the other would not retain its designation unless its
sponsor provided evidence that the drug may demonstrate substantial improvement over the
recently approved drug. Additionally, if the sponsor recognizes that the development program
designated as breakthrough therapy will no longer be pursued, the sponsor should inform the
Agency of this change.
When breakthrough therapy designation is no longer supported by emerging data or the
designated drug development program is no longer being pursued, the Agency may choose to
send a letter notifying the sponsor that the program is no longer designated as a breakthrough
therapy development program. Consistent with FDA’s commitment to communicate frequently,
and in an interactive manner, with sponsors of drugs designated as breakthrough therapies, FDA
will notify the sponsor of its intent to rescind and will offer the sponsor an opportunity to justify
its product’s continued designation. FDA recognizes that sponsors of products that have had
their breakthrough therapy designation rescinded because available data no longer support the
designation may still have sufficient evidence after completion of the drug development program
to support marketing approval.
C.

Process for Priority Review Designation

FDA determines whether an application qualifies for priority review (versus standard review) for
every application, not just when priority review is requested by the applicant. However, an
applicant may expressly request priority review as described in the following sections.
1.

When to Send a Designation Submission

Sponsors may request priority review designation when they submit an original BLA, NDA, or
efficacy supplement. The Agency does not anticipate that priority review designation requests
will be made after the filing of a BLA, NDA, or efficacy supplement.
2.

Where to Send a Designation Submission

Priority review designation requests may be submitted with the original BLA, NDA, or efficacy
supplement to the attention of the appropriate review division or office in CDER or CBER.
3.

Content of a Designation Submission

Priority review designation requests should contain the following information:
x

Identification of the submission in the cover letter as a REQUEST FOR PRIORITY
REVIEW DESIGNATION in bold, uppercase letters.

In the cover letter of the submission, the name of the sponsor’s contact person and the
contact person’s address, email address, telephone number, and fax number.

Contains Nonbinding Recommendations
x

If available, for drug products, the proprietary name and active ingredient and for
biological products, the proper name and proprietary name.

The proposed indication(s).

A concise summary of information that supports the priority review designation request,
including the following:
o The basis for considering the drug to be intended to treat a serious condition
o The basis for the assertion that the drug would be a significant improvement in the
safety or effectiveness of the treatment, prevention, or diagnosis of a serious
condition
4.

FDA Response

FDA will inform the applicant in writing of a priority review designation by day 60 of the
review. The division will inform the applicant in writing of a standard review designation by
day 74 of the review. Applications that are not filed do not receive a review designation.
5.

Continued Priority Review Designation

After priority review designation is assigned, the timeline will not change during the first review
cycle, even if a redetermination of review status is made because of approval of other drugs,
availability of new data, or submission of a request for formal dispute resolution by the
applicant. In addition, applications filed over protest are assigned a standard review. If the
application is resubmitted after FDA’s refuse-to-file decision or if the application is withdrawn
before FDA’s action and resubmitted, FDA will make its determination of review designation
based on the resubmitted application.

Contains Nonbinding Recommendations
APPENDIX 2: PROCESSES FOR ROLLING REVIEW
This appendix describes general processes applicable to the submission and review of portions of
an application, a feature of fast track designation (see section V.B.2.) and breakthrough therapy
designation (see section V1.B.3.).
A.

Agreement on Proposal

Sponsors obtain preliminary Agency agreement on the proposal at the pre-BLA or pre-NDA
meeting or earlier for products with breakthrough therapy designation (e.g., end-of-phase 2
meeting). At the meeting, the sponsor and the review division should discuss: (1) the data
that will be used to support effectiveness, (2) the schedule for submission of each portion of
the BLA or NDA, and (3) a description of portions of the application to be submitted
separately.
A request to submit portions of an application ordinarily should be included in the
information package for the pre-BLA or pre-NDA meeting. If a sponsor seeks to submit
portions of an application to the IND after the pre-BLA or pre-NDA meeting, the sponsor
should make such a request and provide a proposed schedule for submission of portions of an
application to the IND as soon as possible.
A request for submission of portions of an application should be sent as an amendment to the
IND; attach Form FDA 1571. The amendment should be clearly identified as a REQUEST
FOR SUBMISSION OF PORTIONS OF AN APPLICATION in bold, uppercase letters.
FDA responds to sponsors’ requests for submission of portions of an application by letter.
FDA also responds to changes to an agreement to accept portions of an application by letter.
B.

Portions of an Application Eligible for Early Submission

Generally, the Agency accepts for submission a complete section of a BLA or NDA only,
such as the entire CMC section, toxicology section, or clinical section. 45 A section of a BLA
or NDA should be submitted for review in a form adequate to have been included in a
complete BLA or NDA submission. Drafts should not be included in a submission; if final
reports need to be updated, the applicant should submit a formal amendment to the BLA or
NDA with the revised information. Occasionally, the Agency may, in its discretion, accept
less than a complete section if the Agency determines that such a subsection would constitute
a reviewable unit and be useful in making the review process more efficient (e.g., less than a
complete section could be a CMC section lacking final consistency lot data and long-term
stability data, a toxicology section lacking chronic toxicology data, final study reports for
some or all of the principal controlled trials without integrated summaries). The sponsor
should confirm these subsections are final reports.
At the pre-BLA or pre-NDA meeting, the Agency and the sponsor should work together to
clearly define the parameters of accepting an incomplete section and to determine whether
45

Form FDA 356h may be a useful guide to items in a BLA or NDA.

Contains Nonbinding Recommendations
FDA could conduct a meaningful review of the submission before receiving the missing
information.
C.

Submission of User Fees

A sponsor is required to pay applicable fees as stated in section 736 of the FD&C Act before
FDA may commence review of any portion of an application. The applicant should submit Form
FDA 3397 with applicable user fees and follow the same procedures as those followed when a
complete application is submitted.
D.

Commencement of Review

If FDA accepts a portion of an application, this does not necessarily mean that review will
commence or proceed before the complete application is submitted. Actual commencement and
scheduling of review depends on many factors, including staffing, workload, competing
priorities, timeline for completing the application, and the perceived efficiency of commencing
review before receipt of the complete submission.
E.

Calculation of Review Time

The review clock will not begin until the applicant informs the Agency that a complete BLA
or NDA was submitted. 46 After the Agency is notified of the complete application, we will
make a filing determination within the usual time. 47

Section 506(d)(2) of the FD&C Act provides that any time period for review of human drug applications shall not
apply until the date on which the application is complete.
47
See § 314.101, CDER MAPP 6025.4, Good Review Practice: Refuse to File, available on the Internet at
http://www.fda.gov/downloads/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/manualofpoliciespr
ocedures/ucm370948.htm and CBER SOPP 8404, Refusal to File Procedures for Biologic License Applications
(August 27, 2007), available on the Internet at
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ProceduresSOPPs/ucm07
3474.htm.

File Type	application/pdf
File Title	Expedited Programs for Serious Conditions – Drugs and Biologics
Subject	Expedited Programs, Serious Conditions, Drugs, Biologics, biological products
Author	FDA/CDER CBER
File Modified	2024-03-12
File Created	2024-03-12