Priority Review Designation Request

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

DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 60 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit electronic comments to http://www.regulations.gov. Submit written
comments to the Division of Dockets Management (HFA-305), Food and Drug Administration,
5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with
the docket number listed in the notice of availability that publishes in the Federal Register.
For questions regarding this draft document contact (CDER) Office of Medical Policy at 301796-2500, or (CBER) Office of Communication, Outreach and Development at 800-835-4709 or
301-827-1800.
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)

June 2013
Procedural

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
[email protected]
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
and/or
Office of Communication, Outreach and
Development, HFM-40
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Rockville, MD 20852-1448
Tel: 800-835-4709 or 301-827-1800
[email protected]
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/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)
June 2013
Procedural

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TABLE OF CONTENTS

I.

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

II.

BACKGROUND ............................................................................................................... 2

III.

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

A.

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

B.

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

C.

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

IV.

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

V.

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

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

B.

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

VI.

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

A.

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

B.

Features of Breakthrough Therapy Designation ...................................................................... 12

VII.

ACCELERATED APPROVAL ..................................................................................... 14

A.

Qualifying Criteria for Accelerated Approval .......................................................................... 15

B.

Accelerated Approval Endpoints................................................................................................ 16

C.

Evidentiary Criteria for Accelerated Approval ........................................................................ 17

D.

Conditions of Accelerated Approval .......................................................................................... 20

VIII. PRIORITY REVIEW DESIGNATION ....................................................................... 22
A.

Qualifying Criteria for Priority Review Designation ............................................................... 22

B.

Features of Priority Review Designation ................................................................................... 23

IX.

GENERAL CONSIDERATIONS ................................................................................. 23

A.

Manufacturing and Product Quality Considerations ............................................................... 23

B.

Nonclinical Considerations ......................................................................................................... 24

C.

Clinical Inspection Considerations ............................................................................................. 24

APPENDIX 1: PROCESSES FOR FAST TRACK, BREAKTHROUGH THERAPY, AND
PRIORITY REVIEW DESIGNATIONS ................................................................................. 25
A.

Process for Fast Track Designation............................................................................................ 25

B.

Process for Breakthrough Therapy Designation....................................................................... 27

C.

Process for Priority Review Designation ................................................................................... 29

APPENDIX 2: PROCESSES FOR ROLLING REVIEW ...................................................... 32
A.

Agreement on Proposal ............................................................................................................... 32

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B.

Portions of an Application Eligible for Early Submission ....................................................... 32

C.

Submission of User Fees .............................................................................................................. 33

D.

Commencement of Review .......................................................................................................... 33

E.

Calculation of Review Time ........................................................................................................ 33

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Guidance for Industry 1
Expedited Programs for Serious Conditions––Drugs and Biologics

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This draft guidance, when finalized, will represent 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.

I.

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). This
guidance for industry provides 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.
The provisions of this guidance, when finalized, will replace the current guidance for industry
entitled Fast Track Drug Development Programs—Designation, Development, and Application
Review (issued January 2006). The provisions of this guidance relating to available therapy,
when finalized, will replace the current guidance for industry entitled Available Therapy (issued
July 2004). 4
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.

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
Section III.A.1 explains that all references to serious conditions include life-threatening conditions.
4
We update and issue guidances periodically. We recommend you check the FDA Web site to ensure that you have
the most up-to-date version of a guidance. The guidances referenced in this document are available on the Drugs
guidance page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm and
the Biologics guidance page at
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
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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 21 CFR part
312, subpart E. 5 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 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 risk (and uncertainty about benefit) for a treatment for a serious condition where there is
an unmet medical need.
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 in more detail below. As referenced above, the criteria for all four of these expedited
programs draw on the same principle of addressing unmet medical need in the treatment of a
serious condition, which is discussed below.
A.

Serious Condition

1.

Whether a Condition Is Serious

FDA generally intends to interpret the term “serious” consistent with how it has done so in the
past for the purposes of accelerated approval, 6 fast track designation, 7 and expanded access to
investigational drugs for treatment use. 8 A serious disease or condition is defined in the
expanded access regulations as:
“a disease or condition associated with morbidity that has substantial impact on day-today 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
5

21 CFR part 312, subpart E; 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).
6
Food and Drug Administration, Final Rule, New Drug, Antibiotic, and Biological Drug Product Regulations;
Accelerated Approval (57 FR 58942, December 11, 1992).
7
Guidance for Industry: FastTrack Drug Development Program — Designation, Development, and Application
Review (which will be superceded by this final guidance and withdrawn).
8
21 CFR part 312, subpart I.
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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.” 9
This definition is derived from and consistent with the descriptions of the term in the preamble to
the accelerated approval proposed rule and the fast track guidance.
Note: For the purposes of this guidance, FDA considers the term condition to include a
disease or illness. All conditions meeting the definition of life-threatening as set forth at
21 CFR 312.81(a) would also be serious conditions.
2.

Whether the Drug Is Intended to Treat a Serious Condition

As referenced in Section IV, as a general matter, 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 aspect of a condition, such
as a direct effect on a serious manifestation or symptom of a condition, or other intended effects,
including:
•

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 improve or prevent a serious treatment-related side effect (e.g.,
serious infections in patients receiving immunosuppressive therapy)

•

A product intended to avoid a serious adverse effect associated with available therapy for
a serious condition (e.g., less cardiotoxicity than available cancer therapy)
B.

Available Therapy

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

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

•

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

Approval or Licensure: Only in rare 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 evidence in the
published literature (e.g., certain established oncologic treatments).
9

21 CFR 312.300(b)(1).
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U.S. Standards of Care: 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. FDA’s available therapy determination generally
focuses only 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. In the absence of a wellestablished and documented SOC, FDA may consult with special government employees or
other experts for advice in assessing whether an approved therapy is relevant to the current SOC.
When a drug development program targets a subset of a broader disease population (e.g., a
subset identified by a genetic or proteomic marker), the SOC for the broader population, if there
is one, generally is considered available therapy for the subset.

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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 the 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).

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A drug granted accelerated approval based on a surrogate or clinical endpoint and for which
clinical benefit has not been verified is not considered available therapy.

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A drug approved under accelerated approval with restricted distribution and a drug 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) would
be considered available therapy only if the study population for the new drug would be eligible
to receive the approved drug under the restricted distribution program or ETASU REMS.

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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).
1.

Where There Is No Available Therapy

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

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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:
•

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

•

Has an improved effect on a serious outcome(s) of the condition compared to available
therapy (e.g., superiority of the new drug used alone or in combination with available
therapy in an active- or historically-controlled trial assessing an endpoint reflecting
mortality or serious morbidity)

•

Has a benefit for patients who are unable to tolerate available therapy or whose disease
has failed to respond to available therapy, or the treatment can be used effectively with
other critical agents that cannot be combined with available therapy

•

Provides efficacy similar 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 similar safety and efficacy as available therapy but with another 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 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 to available therapy. For
example, 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. For example, infectious disease drugs or targeted cancer therapies with novel mechanisms
of action, although appearing to have comparable efficacy 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-tohead comparisons.
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3.

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

As discussed in Section VII, 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 post-approval confirmatory trials. FDA
may therefore consider products as addressing unmet medical need notwithstanding the
availability of therapies with accelerated approval.

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IV.

OVERVIEW OF EXPEDITED PROGRAMS

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

7

Accelerated Approval
Approval Pathway

Priority Review
Designation

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

• Prescription Drug
User Fee Act of
1992

Act, as amended by section
901 of FDASIA

• A drug that treats a serious
condition AND generally
provides 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 an
effect on 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)

• 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
• Any supplement
that proposes a
labeling change
pursuant to a
report on a
pediatric study
under 505Ac OR
• An application
for a drug that
has been
designated as a
qualified
infectious disease
productd OR
• Any application
or supplement for
a drug submitted
with a priority
review vouchere

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Comparison of FDA’s Expedited Programs for Serious Conditions
Fast Track
Breakthrough Therapy
Nature of
Designation
Designation
program
When to
• With IND or after
• With IND or after
submit
• Ideally, no later than the
• Ideally, no later than the
pre-BLA or pre-NDA
end-of-Phase 2 meeting
meeting

Priority Review
Designation

• The sponsor should
ordinarily discuss the
possibility of accelerated
approval with the review
division during
development, supporting,
for example, the use of the
planned endpoint as a basis
for approval and discussing
the confirmatory trials.
• Not specified

• With original

Timelines for
FDA response

• Within 60 calendar days of

Features

• Actions to expedite

• All fast track designation

• Approval based on an effect

development and review
• Rolling review

features
• Intensive guidance on
efficient drug
development during IND,
beginning as early as
Phase 1
• Organizational
commitment involving
senior managers
• Designation may be
withdrawn if it no longer
meets breakthrough
therapy qualifying criteria

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

Additional
considerations

receipt of request

• Designation may be
withdrawn if it no longer
meets fast track qualifying
criteria

• Within 60 calendar days

Accelerated Approval
Approval Pathway

of receipt of request

a

• Submission of copies of
promotional materials for
review
• Conduct any required
postapproval trials to verify
and describe the anticipated
clinical benefit or effect on
IMM
• Subject to expedited
withdrawal

BLA, NDA, or
efficacy
supplement

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

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

Designation applies to a combination of a drug (either alone or in combination with other drugs) and the specific use for which it is being studied.
Where appropriate, designation may be granted to development of a new use of an FDA-approved drug.
b
Title VIII of FDASIA entitled “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.
c
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 to be 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.
d
See footnote b above.
e
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 (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.

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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 section describes the qualifying
criteria (italicized terms) and the features (e.g., benefits) of fast track designation. Appendix 1
describes the fast track designation process.
A.

Qualifying Criteria for Fast Track Designation

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 in 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

1.

Actions to Expedite Development and Review

There are opportunities for frequent interactions with the review team for a fast track product.
These include FDA-sponsor meetings, including pre-IND, end of Phase 1, and end of Phase 2
meetings to discuss study design, extent of safety data required to support approval, doseresponse concerns, use of biomarkers, and other meetings as appropriate (i.e., 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.
2.

Submission of Portions of an Application (Rolling Review)

If FDA determines, after preliminary evaluation of clinical data submitted by the sponsor, that
a fast track product may be effective, the Agency shall evaluate for filing, and may consider

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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.” This section describes the qualifying criteria (italicized terms) and the features
(e.g., benefits) of breakthrough therapy designation. Appendix 1 describes the breakthrough
therapy designation process.
A.

Qualifying Criteria for Breakthrough Therapy Designation

1.

Serious Condition

See Section III.A.
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
would represent substantial improvement over available therapies for the treatment of a serious
condition. Assessment of the treatment effect for the purposes of breakthrough therapy
designation will be based on preliminary clinical evidence, which could include early clinical
evidence of both clinical benefit and an effect on a mechanistic biomarker (generally derived
from Phase 1 and 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 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 and shows superiority, 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
10

Section 506(d)(1) of the FD&C Act.
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this kind early in development. Other types of clinical data that could also be persuasive include
studies comparing the new treatment with historical experience (generally, FDA expects such
data would be persuasive only if there is a large difference between the new treatment and
historical experience). 11
4.

May Demonstrate Substantial Improvement on Clinically Significant Endpoint(s)

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: To determine whether the improvement over available therapy is
substantial is a matter of judgment and depends on both the magnitude of the treatment effect,
which could include duration of the effect, and the importance of the observed clinical outcome.
In general, the preliminary clinical evidence should show a clear advantage over available
therapy. Such improvement will be clear when there is no available therapy or when available
therapy shows only a modest response and the new therapy shows an effect on an important
outcome. Where there is an effective available therapy, showing substantial improvement is
more challenging.
Approaches to demonstrating preliminary clinical evidence of substantial improvement include:
•

Direct comparison of a new drug to available therapy (or to no treatment if none exists)
showing a much greater or more important response (e.g., complete response where the
control treatment results in partial response). 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 notreatment controlled study.

•

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 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 treats the underlying cause of the disease, in contrast to available therapies
that treat only symptoms of the disease, and preliminary clinical evidence shows
significant efficacy. In this case, the treatment effect is entirely new (i.e., has not been
observed with available therapies). For example, a drug that targets a defective protein
that is the underlying cause of a disease (whereas current therapies only treat the
symptoms of the disease).

11

Sponsors contemplating the use of historical controls should consult FDA’s guidance for industry E10 Choice of
Control Group and Related Issues in Clinical Trials (May 2001, ICH) for more detailed discussions.
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•
•

The new drug reverses 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 events
compared to 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:
•

An effect on an established surrogate endpoint

•

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)

•

An effect on a pharmacodynamic biomarker(s) that does not meet criteria for an
acceptable surrogate endpoint, but strongly suggests the potential for a clinically
meaningful effect on the underlying disease

•

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

In a breakthrough therapy designation request, the sponsor should provide justification for why
the endpoint, biomarker, or other findings should be considered clinically significant.
B.

Features of Breakthrough Therapy Designation

1.

All Fast Track Designation Features

Section 902 of FDASIA instructs FDA to take actions appropriate to expedite the development
and review of a breakthrough therapy. Because a drug that qualifies for breakthrough therapy
designation would also meet the standard for fast track designation, FDA has determined that it
would be appropriate for the features of fast track designation to be available to a drug
designated as a breakthrough therapy (see Section V.B).
2.
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 to 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 in order to
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meet the statutory standard for approval. 12 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 an efficient clinical trial or trials in a number of ways. FDA will seek to
ensure that the sponsor of a product designated as a breakthrough therapy receives timely advice
and interactive communications in order to help the sponsor design and conduct a development
program as efficiently as possible. During these interactions, the Agency may suggest, or a
sponsor can propose, alternative clinical trial designs (e.g., adaptive designs, an enrichment
strategy, use of historical controls) that may result in smaller trials or more efficient trials that
require less time to complete. Such trial designs could also help minimize the number of patients
exposed to a potentially less efficacious treatment (i.e., the control group treated with available
therapy).
FDA anticipates that the review team and the sponsor will meet 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).
3.

Organizational Commitment Involving Senior Managers

FDA intends to expedite the development and review of a breakthrough therapy by, where
appropriate, intensively involving senior managers and experienced review staff in a proactive
collaborative, cross-disciplinary review. Where appropriate, FDA also intends to assign a crossdisciplinary project lead for the review team to facilitate an efficient review of the development
program. The cross-disciplinary project lead will serve as a scientific liaison between the
members of the review team (e.g., clinical; pharmacology-toxicology; chemistry, manufacturing,
and controls (CMC); compliance; biostatistics) for coordinated internal interactions and
coordinated communications with the sponsor through the review division’s Regulatory Health
Project Manager.
If a sponsor has not requested breakthrough therapy designation, FDA may suggest that the
sponsor consider submitting a request if: (1) after reviewing submitted data and information
(including preliminary clinical evidence), the Agency thinks the drug development program may
meet the criteria for breakthrough therapy designation and (2) the remaining drug development
program can benefit from the designation.

12

Section 505(d) of the FD&C Act; Section 351(a) of the Public Health Service Act.
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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 condition . . . upon a determination that the
product has an effect on a surrogate endpoint that is reasonably likely to predict clinical
benefit, or an effect on a clinical endpoint that can be measured earlier than an effect on
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.
Accelerated approval is usually contingent on a sponsor’s agreement to conduct additional postapproval studies to verify and describe the drug’s clinical benefit (see Sections VII.D.2 and
VII.D.3). 13
This section describes the qualifying criteria, relevant terms (italicized terms), and the conditions
of accelerated approval. The FDASIA provisions facilitate somewhat broader use of accelerated
approval to expedite patient 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). Finally, 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.1). 14
The accelerated approval pathway is most often useful in settings in which the disease course is
long and an extended period of time is required to measure the intended clinical benefit of a
drug, even if the effect on the surrogate or intermediate clinical endpoint occurs rapidly. For
example, accelerated approval has been used extensively in drug development for a variety of
cancers and human immunodeficiency virus (HIV) disease—diseases in which the goal of
therapy is generally to improve survival or decrease morbidity and the duration of the typical
disease course requires lengthy and sometimes large trials to demonstrate a clinical or survival
benefit.
Accelerated approval is generally less useful in more acute disease settings in which therapy is
intended to provide a more near-term clinical benefit. In such settings, even if there are
13

FDCA 506(c)(2)(A).
FDCA 506(c)(1)(B). FDA regulations 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.”
14

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potentially predictive surrogate endpoints or intermediate clinical endpoints, there may be little
or no time advantage for studies evaluating a surrogate or intermediate endpoint compared to
studies evaluating the intended clinical benefit.
FDA encourages sponsors to communicate with the Agency early in development concerning the
potential eligibility of the drug for accelerated approval, proposed surrogate or intermediate
clinical endpoints, clinical trial designs, and study planning and conduct of confirmatory trials.
A.

Qualifying Criteria for Accelerated Approval

At the time a product is given accelerated approval, there generally will be uncertainty about
whether a surrogate endpoint or intermediate clinical endpoint predicts the drug’s ultimate
anticipated clinical benefit. The principal risk of this approach is the possibility that patients will
be exposed to a drug that will ultimately not be shown to provide an actual clinical benefit. In
addition, there may be fewer, smaller, or shorter clinical trials than is typical for a drug with
traditional approval, which for example could mean there is less information about the
occurrence of rare adverse events. For these reasons, accelerated approval is limited to a drug
intended to treat a serious condition which appears to provide some 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. 15 The accelerated
approval provision of section 901 of FDASIA (amending section 506 of the FD&C Act) requires
FDA to “tak[e] into account . . . the availability or lack of alternative treatments.”
Amended section 506(c) may reasonably be interpreted as providing additional flexibility as
compared to the regulations. Specifically, section 506(c) broadens use of the accelerated
approval pathway to cases in which the advantage of a new drug over available therapy may not
be a direct therapeutic advantage, but is a clinically important improvement from a patient and
public health perspective. The discussion of unmet medical need in Section III.C.2 provides
examples of situations in 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 therapeutic
advantage. Section III.B describes what constitutes available therapy for purposes of
determining whether a drug provides a meaningful advantage.

15

21 CFR 314.500 and 601.40.
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B.

Accelerated Approval Endpoints

There are two types of endpoints that can be used as a basis for accelerated approval: (1) a
surrogate endpoint that is considered reasonably likely to predict clinical benefit; and (2) 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 (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, which
could be used for traditional approval), a surrogate endpoint that is reasonably likely to predict a
drug’s intended clinical benefit (which could be used 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 thus cannot be used to support traditional or accelerated approval of a marketing
application).
HIV viral load, as evidenced by a laboratory measure of HIV in plasma, has been shown to
correlate with morbidity and mortality associated with HIV disease, but is not a direct measure of
clinical benefit. Prolonged suppression of viral load is known to reliably predict an effect on
survival.
2.
Intermediate Clinical Endpoints (clinical endpoints that can be measured earlier
than an effect on irreversible morbidity or mortality)
For purposes of accelerated approval, an intermediate clinical endpoint is a measurement of a
therapeutic effect that is considered reasonably likely to predict the clinical benefit of a drug,
such as an effect on IMM.
A threshold question is whether the demonstrated therapeutic effect alone would be a basis for
traditional approval. For example, traditional approval would be appropriate where the effect is
modest, but a sufficiently meaningful benefit within the context of the disease to provide a
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favorable risk-benefit profile. If the therapeutic effect is not a clinical benefit and a basis for
traditional approval, accelerated approval could be an option if there is a basis for concluding
that the therapeutic effect is reasonably likely to predict the ultimate clinical benefit of a drug.
FDA has limited experience with accelerated approvals based on intermediate clinical endpoints.
However, we believe intermediate clinical endpoints generally would be used to support
accelerated approval in the following types of situations:
•

The study results for a clinical endpoint demonstrate a therapeutic effect that would not
support traditional approval because:
o The effect is not a clinical benefit
o The effect is only a modest benefit within the context of the disease that alone
would not justify the risks associated with the drug, but there is an evidentiary
basis to conclude that the effect is reasonably likely to predict an effect on IMM
or other clinical benefit that would be a basis for traditional approval

•

A clinical endpoint demonstrates a relatively short-term clinical benefit in a chronic
disease setting in which it is essential to confirm longer-term durability of the clinical
benefit for traditional approval but the short-term benefit is 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)

FDA expects that most demonstrations of clinical benefit would be a basis 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. 16 For effectiveness, the standard is
substantial evidence based on adequate and well-controlled clinical investigations. 17 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. 18 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 (and ensure that remaining doubts about the relationship of the

16

Section 505(d) of the FD&C Act.
Section 505(d)(5) of the FD&C Act.
18
Section 505(d)(1) of the FD&C Act.
17

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effect on the surrogate to clinical benefit are resolved by additional post-approval studies). 19 An
application for accelerated approval should also include evidence that a surrogate or intermediate
clinical endpoint is reasonably likely to predict the intended clinical benefit of a drug.
1.

Whether an Endpoint Is “Reasonably Likely to Predict” Clinical Benefit

Whether an endpoint is reasonably likely to predict clinical benefit is a function of the biological
plausibility of the relationship between the disease, 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.” 20 Evidence of
pharmacologic activity alone is not sufficient, however. 21 Clinical data should be provided to
support the assertion that a relationship of the surrogate or intermediate clinical endpoint to the
outcome is reasonably likely, and should be relevant to the relationship between the specific
endpoint to be used and the specific intended clinical benefit of the drug.
Whether a drug effect on a given endpoint is reasonably likely to predict clinical benefit is a
matter of judgment. FDA considers all relevant evidence and weighs the uncertainty against the
severity of the disease to be treated and the lack of available therapy. On a case-by-case basis,
FDA will make informed judgments using both internal and external expertise. This guidance
provides an overview of some of the important factors to consider in identifying and assessing
the predictive potential of surrogate or intermediate clinical endpoints. However, this guidance
does not address clinical evidence requirements because they are not readily generalizable.
a.

Understanding of the disease process

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

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•

The underlying cause of the disease (e.g., elevated uric acid and gout, elevated blood
pressure and hypertensive cardiovascular disease, low thyroxin levels and
hypothyroidism)

•

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)

•

The state of the pathophysiologic pathway leading to the clinical outcome (e.g.,
replacement of a missing enzyme or clotting factor)

19

Section 506(c) of the FD&C Act. Final Rule, New Drug, Antibiotic, and Biological Drug Product Regulations;
Accelerated Approval (57 FR at 58948, December 11, 1992).
20
Section 506(c)(1)(B) of the FD&C Act, as amended by section 901 of FDASIA.
21
Food and Drug Administration, Final Rule, New Drug, Antibiotic, and Biological Drug Product Regulations;
Accelerated Approval (57 FR 58942, December 11, 1992).
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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 identify a surrogate endpoint. 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
alone will not reasonably predict the disease course or treatment results.
Some effects on well-established, disease-related markers may have little or no ability to predict
clinical benefit. For example, fever occurs with most infectious diseases but lowering a patient’s
body temperature with a non-steroidal anti-inflammatory drug does not predict the drug’s effect
on the disease (although it could be a pertinent biomarker for an antibiotic). Similarly, in
prostate cancer, increased levels of prostate-specific antigen (PSA) are the result of advancing
tumor burden. Therefore, PSA is correlated with the progression of prostate cancer and risks of
mortality. However, PSA is not the mechanism through which the disease causes morbidity; so,
the effect of a drug on lowering PSA cannot necessarily be relied upon to predict the drug’s
clinical benefit.
b.
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 is critical. Sometimes this relationship can be assessed epidemiologically but it is most
persuasively established by knowing that a drug that affects the surrogate also affects a clinical
outcome. Thus, lowering blood pressure has been shown repeatedly to reduce the incidence of
stroke and cardiovascular disease in people with hypertension. Similarly, killing infecting
bacteria or viruses leads to cure of 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.
Following are examples of factors to consider in identifying and assessing a surrogate endpoint:

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•

Whether there is reliable and consistent epidemiologic evidence supporting the
relationship between the endpoint and the intended clinical benefit 22

•

How precisely the epidemiologic relationship between the endpoint and clinical outcome
is defined. (The more precise the relationship, the stronger the basis for concluding that
an effect on the endpoint would have a reasonably well-defined effect on the clinical
outcome)

22

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.
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•

Whether the effect on the endpoint has been shown to predict a clinical benefit with drugs
in the same or a closely related pharmacological class

•

Whether the effect on the endpoint has been shown to predict clinical benefit with other
drugs in the class for the disease being treated

If an endpoint has failed to predict clinical benefit in a properly designed trial for a drug in the
same pharmacologic class, or in the same disease or a related disease, that weighs against
reliance on the endpoint as a basis for accelerated approval.
D.

Conditions of Accelerated Approval

1.

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. 23 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. 24
2.

Confirmatory Trials

For drugs granted accelerated approval, postmarketing confirmatory trials are generally required
to verify and describe the anticipated clinical benefit or effect on IMM. These trials must be
completed with due diligence. 25 Where confirmatory trials verify clinical benefit, FDA will
generally terminate the requirement. 26
Generally, the confirmatory clinical trial would evaluate a clinical endpoint that directly
measures the clinical benefit. It is a possibility in some cases, however, that additional
evaluation of a surrogate endpoint (e.g., for a longer period), could be persuasive evidence of a
clinical benefit. For example, an effect of relatively short duration on a surrogate endpoint may
be reasonably likely to predict clinical benefit, supporting accelerated approval. A trial
demonstrating that the effect on the same surrogate endpoint persists for an extended duration
may be known to reliably predict such clinical benefit.
FDA’s accelerated approval regulations provide that postmarketing confirmatory trials to verify
clinical benefit would usually be underway at the time of accelerated approval. 27 Ideally,
23

21 CFR 314.550 and 601.45.
21 CFR 314.550 and 601.45.
25
FD&C Act 506(c)(3)(A); 21 CFR 314.510 and 601.41.
26
21 CFR 314.560 and 601.46.
27
21 CFR 314.510 and 601.41.
24

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confirmatory trials will be underway even earlier -- at the time a marketing application is
submitted. This will help to ensure the confirmatory trials are completed with due diligence and
that it will be known as soon as possible whether the drug provides actual clinical benefit.
The design of confirmatory trials should be part of a comprehensive drug development plan and
should be discussed with FDA early in the development process. Applicants should include
timelines in their development plans to help ensure postapproval confirmatory trials are
completed with due diligence. There is concern that the availability of drugs to patients
following accelerated approval may interfere with patient accrual to a confirmatory trial,
especially when the confirmatory trial is in the same disease population as the population for the
drug’s accelerated approval indication. For this reason, a confirmatory trial may be conducted in
a study population that differs from the population for which accelerated approval was granted.
This is the usual case in oncology.
Another approach is to use an interim analysis of the surrogate endpoint data as the basis for
accelerated approval, with continuation of the randomized trials during the time period when the
surrogate endpoint and interim safety data are being: (1) analyzed, (2) prepared for submission to
FDA, and (3) reviewed by FDA. When the ultimate clinical outcome can be expected over this
additional timeframe, the data to verify the clinical benefit may be 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 28, for example:
•

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

•

Other evidence demonstrates 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

•

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

28

FDCA 506(c)(3). There are additional grounds for withdrawal in Subparts E and H. See 21 CFR 314.530(a) and
601.43(a).
21

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750
751
752
753
754
755
756
757
758
759
760
761
762
763
764
765
766
767
768
769
770
771
772
773
774
775
776
777
778
779
780
781
782
783
784
785
786
787
788
789
790

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
voluntarily request withdrawal of approval under 21 CFR 314.150(d) or notify the applicant of
FDA’s proposal to withdraw approval in a notice of opportunity for hearing (NOOH). The
NOOH will generally state the proposed grounds for withdrawal of approval. 29 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. 30 An
applicant may also voluntarily request the Agency to withdraw approval of an application
approved under accelerated approval. 31
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, there are specific statutory provisions that 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 (italicized terms) and the features (e.g., benefits) of priority
review designation. Appendix 1 describes the priority review designation process.
A.

Qualifying Criteria for Priority Review Designation

1.

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 whether the proposed drug would be a significant
improvement in the safety or effectiveness of the treatment, diagnosis, or prevention of a serious
condition. Significant improvement may be illustrated by the following examples:
•

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

•

Elimination or substantial reduction of a treatment-limiting drug reaction

•

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

29

21 CFR 314.530(b) and 601.43(b).
21 CFR 314.530(c)(1) and 601.43(c)(1).
31
21 CFR 314.150(c) and 21 CFR 601.5(a).
30

22

Contains Nonbinding Recommendations
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791
792
793
794
795
796
797
798
799
800
801
802
803
804
805
806
807
808
809
810
811
812
813
814
815
816
817
818
819
820
821
822
823
824
825
826

•

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 related to either safety or effectiveness. Alternatively, sponsors could show the
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. 32
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 (compared to 10 months under standard review).
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 the sponsor respond promptly to FDA’s inquiries. This applies to formal
meetings and related inquiries, written correspondence, and other interactions. In addition to the
many types of formal meetings 33 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 will probably
need to pursue a more rapid manufacturing development program to accommodate the
accelerated pace of the clinical program. The sponsor’s product quality team and CMC teams
should initiate early communication with FDA to ensure that the manufacturing development
programs and timing of submissions meet the Agency’s expectations for licensure or marketing
approval. 34

32

Sponsors contemplating the use of historical controls should consult the ICH guidance for industry E10 Choice of
Control Group and Related Issues in Clinical Trials (May 2001, ICH) for more detailed discussions.
33
See the guidance for industry Formal Meetings Between the FDA and Sponsors or Applications.
Also see the CDER 21st Century Review Process Desk Reference Guide accessible at
http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ManualofPoliciesProcedures/UCM218757.pdf.
34
See the guidance for industry IND Meetings for Human Drugs and Biologics Chemistry, Manufacturing, and
Controls Information.
23

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827
828
829
830
831
832
833
834
835
836
837
838
839
840
841
842
843
844
845
846
847
848
849
850
851
852
853
854
855
856
857
858
859
860
861
862
863
864

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, especially with regard to manufacturing facilities,
lifecycle process validation (including scale-up and comparability), methods validation, stability
studies, and potency studies if applicable. The proposal should also include a timeline for
development of the manufacturing capabilities with goals aligned with the clinical development
program. The applicant should ensure that the manufacturing process is sufficiently developed
in order to support the CMC section. After the initial discussion following designation, frequent
communication during development will generally facilitate meeting manufacturing development
and product quality goals.
The 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 planning.
Coordination with the sponsor and contract manufacturers may be necessary to ensure facilities
(e.g., the manufacturing process and equipment) are ready for inspection (e.g., during review of
the clinical section of the application). A comprehensive meeting with FDA’s product quality
review and evaluation offices in advance of submission may facilitate quality assessment of
products designated for expedited programs.
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
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. Inspections should be
scheduled 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.

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865
866
867
868
869
870
871
872
873
874
875
876
877
878
879
880
881
882
883
884
885
886
887
888
889
890
891
892
893
894
895
896
897
898
899
900
901
902
903
904
905
906
907
908
909

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

1.

When to Send a Designation Submission

Sponsors may submit fast track designation requests when the IND is first submitted or at any
time thereafter before receiving marketing approval of its 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, requests
should ordinarily occur no later than the sponsor's pre-BLA or pre-NDA meeting with the
Agency because many of the features of fast track designation will not apply after that time.
2.

Where to Send a Designation Submission

The IND or amendment should be sent to the attention of the appropriate review division or
office in CBER or CDER.
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):
•

If the fast track designation request is submitted to the sponsor’s IND as an amendment,
the cover letter should indicate the submission as a REQUEST FOR FAST TRACK
DESIGNATION in bold, uppercase letters. If the request is submitted with an initial
IND, the cover letter should indicate the submission 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 include the name of the sponsor’s contact person,
including the person’s address, email address, telephone number, and fax number.

•

If applicable, the IND application number should be noted.

•

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

•

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

•

The proposed indication(s).
25

Contains Nonbinding Recommendations
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910
911
912
913
914
915
916
917
918
919
920
921
922
923
924
925
926
927
928
929
930
931
932
933
934
935
936
937
938
939
940
941
942
943
944
945
946
947
948
949
950
951
952
953
954

•

A concise summary of information that supports the fast track designation request for the
indication being studied, including:
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, include a list of documents previously submitted to the IND that are
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:
•

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 fulfills 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 Fast Track Designation

Over the course of drug development, it is foreseeable that certain products in fast track drug
development programs will not continue to meet the criteria for fast track designation. A drug
product in a fast track development program may not continue to meet the criteria if the drug: (1)
26

Contains Nonbinding Recommendations
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955
956
957
958
959
960
961
962
963
964
965
966
967
968
969
970
971
972
973
974
975
976
977
978
979
980
981
982
983
984
985
986
987
988
989
990
991
992
993
994
995
996
997

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 fulfills 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

1.

When to Send a Designation Submission

Although sponsors may request breakthrough therapy designation at the time of IND submission,
or at any time afterward, 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.” 35 FDA
expects that in most cases breakthrough therapy designation requests would be submitted as an
amendment to the IND, but a sponsor could also submit its request with the original IND.
Ideally, a breakthrough therapy designation request should be received by FDA no later than the
end-of-Phase-2 meetings if any of the features of the 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 does not anticipate that breakthrough therapy
designation requests will be made after the submission of an original BLA or NDA or a
supplement.
2.

Where to Send a Designation Submission

The IND or amendment should be submitted to the attention of the appropriate review division
or office in CBER or CDER.
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):
35

Section 506(a)(1) of the FD&C Act, as amended by section 902 of FDASIA.
27

Contains Nonbinding Recommendations
Draft — Not for Implementation

998
999
1000
1001
1002
1003
1004
1005
1006
1007
1008
1009
1010
1011
1012
1013
1014
1015
1016
1017
1018
1019
1020
1021
1022
1023
1024
1025
1026
1027
1028
1029
1030
1031
1032
1033
1034
1035
1036
1037
1038
1039
1040

•

If the breakthrough therapy designation request is submitted to the sponsor’s IND as an
amendment, the cover letter should indicate the submission as a REQUEST FOR
BREAKTHROUGH THERAPY DESIGNATION in bold, uppercase letters. If the
request is submitted with an initial IND, the cover letter should indicate the submission 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, including
the person’s address, email address, telephone number, and fax number.

•

If applicable, the IND application number should be noted.

•

If available, include, for drug products, the proprietary name and active ingredient and,
for biological products, the proper name and trade 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 sponsor’s breakthrough therapy
designation request for the indication being studied, including:
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. A sponsor should describe the preliminary
clinical evidence, including, for example, justification for the clinical study
endpoint used and a brief description of statistical analyses
•

If applicable, include a list of documents previously submitted to the IND 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 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:

28

Contains Nonbinding Recommendations
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1041
1042
1043
1044
1045
1046
1047
1048
1049
1050
1051
1052
1053
1054
1055
1056
1057
1058
1059
1060
1061
1062
1063
1064
1065
1066
1067
1068
1069
1070
1071
1072
1073
1074
1075
1076
1077
1078
1079
1080
1081
1082
1083
1084

•

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
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.
5.

Continued Designation as a Breakthrough Therapy Development Program

Over the course of drug development, it is foreseeable that certain products in breakthrough
therapy development programs will no longer be considered a breakthrough therapy. For
example, a drug’s 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
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.
C.

Process for Priority Review Designation

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

29

Contains Nonbinding Recommendations
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1085
1086
1087
1088
1089
1090
1091
1092
1093
1094
1095
1096
1097
1098
1099
1100
1101
1102
1103
1104
1105
1106
1107
1108
1109
1110
1111
1112
1113
1114
1115
1116
1117
1118
1119
1120
1121
1122
1123
1124
1125
1126
1127
1128
1129

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.
3.

Content of a Designation Submission

Priority review designation requests should contain the following information:
•

The cover letter included with the request should be clearly identified as a REQUEST
FOR PRIORITY REVIEW DESIGNATION in bold, uppercase letters.

•

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

•

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

•

The proposed indication(s).

•

A concise summary of information that supports the priority review designation request,
including:
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, diagnosis, or prevention of a serious
condition
4.

FDA Response

The Agency 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,
30

Contains Nonbinding Recommendations
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1130
1131
1132
1133
1134

availability of new data, or submission of a request for 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 then resubmitted, FDA will make its determination of review designation based on the
resubmitted application.

31

Contains Nonbinding Recommendations
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1135
1136
1137
1138
1139
1140
1141
1142
1143
1144
1145
1146
1147
1148
1149
1150
1151
1152
1153
1154
1155
1156
1157
1158
1159
1160
1161
1162
1163
1164
1165
1166
1167
1168
1169
1170
1171
1172
1173
1174
1175
1176
1177

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).
A.

Agreement on Proposal

Sponsors obtain preliminary Agency agreement on the proposal at the pre-BLA or pre-NDA
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 for the product in a fast track drug development program; attach Form FDA 1571. The
amendment should be clearly identified as a “REQUEST FOR SUBMISSION OF
PORTIONS OF AN APPLICATION” in bold uppercase letters. A sponsor may apply for
fast track designation and submission of portions of a BLA or NDA at the same time. In such
cases, sponsors should submit requests as one amendment to the IND. 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. 36 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, an acute 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
36

Form FDA 356h may be a useful guide to items in a BLA or NDA.
32

Contains Nonbinding Recommendations
Draft — Not for Implementation

1178
1179
1180
1181
1182
1183
1184
1185
1186
1187
1188
1189
1190
1191
1192
1193
1194
1195
1196
1197
1198
1199
1200
1201

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 we receive the complete application. Actual commencement and
scheduling of review depends on many factors, including staffing, workload, competing
priorities, timeline for completion of applications, 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. 37 After the Agency is notified of the complete application, we will make a
filing determination within the usual time. 38

37

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.
38
21 CFR 314.101 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.
33