Guidance for Industry 
Expedited Programs for Serious 
Conditions  Drugs and 
Biologics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
May 2014 
Procedural 
 
OMB Control No. 0910-0765 
Current expiration date available at https://www.reginfo.gov 
(Search ICR and enter OMB control number) 
See additional PRA statement in section X of this guidance. 
   
Guidance for Industry 
Expedited Programs for Serious 
Conditions  Drugs and 
Biologics 
 
 
 
Additional copies are available from: 
Office of Communications 
Division of Drug Information, WO51, Room 2201 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave., Silver Spring, MD 20993  
Phone: 301-796-3400; Fax: 301-847-8714 
druginfo@fda.hhs.gov  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
and/or 
 
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Center for Biologics Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave., WO71, Room 3128 
Silver Spring, MD 20993 
Phone: 800-835-4709 or 240-402-7800 
ocod@fda.hhs.gov 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm   
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
 
May 2014 
Procedural 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 1 
III.  CONCEPTS FOR EXPEDITED PROGRAMS ............................................................. 2 
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 ...................................................................... 13 
VII.  ACCELERATED APPROVAL ..................................................................................... 15 
A.  Qualifying Criteria for Accelerated Approval .......................................................................... 16 
B.  Accelerated Approval Endpoints ................................................................................................ 17 
C.  Evidentiary Criteria for Accelerated Approval ........................................................................ 19 
D.  Conditions of Accelerated Approval .......................................................................................... 22 
VIII.  PRIORITY REVIEW DESIGNATION ....................................................................... 24 
A.  Qualifying Criteria for Priority Review Designation ............................................................... 24 
B.  Features of Priority Review Designation ................................................................................... 25 
IX.  GENERAL CONSIDERATIONS ................................................................................. 25 
A.  Manufacturing and Product Quality Considerations ............................................................... 25 
B.  Nonclinical Considerations ......................................................................................................... 26 
C.  Clinical Inspection Considerations ............................................................................................. 27 
D.  Companion Diagnostics ............................................................................................................... 27 
X.  PAPERWORK REDUCTION ACT OF 1995 .............................................................. 27 
APPENDIX 1: PROCESSES FOR FAST TRACK, BREAKTHROUGH THERAPY, AND 
PRIORITY REVIEW DESIGNATIONS ................................................................................. 28 
A.  Process for Fast Track Designation ............................................................................................ 28 
B.  Process for Breakthrough Therapy Designation ....................................................................... 30 
i 
 
  Contains Nonbinding Recommendations 
 
C.  Process for Priority Review Designation ................................................................................... 33 
APPENDIX 2: PROCESSES FOR ROLLING REVIEW ...................................................... 35 
A.  Agreement on Proposal ............................................................................................................... 35 
B.  Portions of an Application Eligible for Early Submission ....................................................... 35 
C.  Submission of User Fees .............................................................................................................. 36 
D.  Commencement of Review .......................................................................................................... 36 
E.  Calculation of Review Time ........................................................................................................ 36 
ii 
 
  Contains Nonbinding Recommendations 
 
Guidance for Industry1 
Expedited Programs for Serious Conditions  Drugs and Biologics 
 
 
This guidance represents the Food and Drug Administrations (FDAs) 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 drugs2 to address unmet medical need in the treatment of a serious or life-
threatening3 condition: fast track designation, breakthrough therapy designation, accelerated 
approval, and priority review designation (see section IV for an overview of the programs).  The 
purpose of this guidance for industry is to provide a single resource for information on FDAs 
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.   
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agencys current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited.  The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required.  
 
II.  BACKGROUND 
 
The programs described in this guidance are intended to help ensure that therapies for serious 
conditions are approved and available to patients as soon as it can be concluded that the 
therapies benefits justify their risks.  The Agency first formally articulated its thinking on 
expediting the availability of promising new therapies in regulations codified at part 312, subpart 
E ( 21 CFR part 312).4  The subpart E regulations are intended to speed the availability of new 
therapies to patients with serious conditions, especially when there are no satisfactory alternative 
therapies, while preserving appropriate standards for safety and effectiveness.  The regulations 
 
1 This guidance has been prepared by the Center for Drug Evaluation and Research (CDER) in cooperation with the 
Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration. 
2 For the purposes of this guidance, all references to drugs or drug products include both human drugs and 
biological drug products regulated by CDER and CBER unless otherwise specified.   
3 Whether a Condition Is Serious explains that all references to serious conditions include life-threatening 
conditions. 
4 Food and Drug Administration, Interim Rule, Investigational New Drug, Antibiotic, and Biological Drug Product 
Regulations; Procedures for Drugs Intended to Treat Life-Threatening and Severely Debilitating Illnesses (53 FR 
41516, October 21, 1988). 
  1 
 
  Contains Nonbinding Recommendations 
 
call for earlier attention to drugs that have promise in treating such conditions, including early 
consultation with FDA for sponsors of such products and efficient trial design, potentially 
relying on well-controlled phase 2 studies for evidence of effectiveness.  The subpart E 
regulations specifically recognize that patients and physicians are generally willing to accept 
greater risks and side effects from treatment of life-threatening and severely debilitating diseases 
than they would for other diseases.  The four principal programs that support these principles are 
fast track designation, breakthrough therapy designation, accelerated approval, and priority 
review designation (referred to in this guidance as the Agencys expedited programs). 
 
FDA has a history of applying the philosophy underlying subpart E to drugs for rare diseases 
through use of the Agencys expedited programs.  FDA recognizes that certain aspects of drug 
development that are feasible for common diseases may not be feasible for rare diseases and that 
development challenges are often greater with increasing rarity of the disease.  FDA will 
continue to apply flexibility in these situations to address particular challenges posed by each 
disease. 
 
III.  CONCEPTS FOR EXPEDITED PROGRAMS 
 
The programs that are the subject of this guidance, fast track designation, breakthrough therapy 
designation, accelerated approval, and priority review, are summarized in section IV and 
described individually in detail in sections V, VI, VII, and VIII.  All four expedited programs 
represent efforts to address an unmet medical need in the treatment of a serious condition, which 
is discussed in the following paragraphs.   
 
A.  Serious Condition 
 
1.  Whether a Condition Is Serious 
 
FDA intends to interpret the term serious as it has done in the past for the purposes of 
accelerated approval5 and expanded access to investigational drugs for treatment use.6  A serious 
disease or condition is defined in the expanded access regulations as follows: 
 
. . . a disease or condition associated with morbidity that has substantial 
impact on day-to-day functioning.  Short-lived and self-limiting 
morbidity will usually not be sufficient, but the morbidity need not be 
irreversible if it is persistent or recurrent.  Whether a disease or condition 
is serious is a matter of clinical judgment, based on its impact on such 
factors as survival, day-to-day functioning, or the likelihood that the 
disease, if left untreated, will progress from a less severe condition to a 
more serious one.7   
 
 
 
5 Food and Drug Administration, Final Rule, New Drug, Antibiotic, and Biological Drug Product Regulations; 
Accelerated Approval (57 FR 58942, December 11, 1992) and Food and Drug Administration, Proposed Rule, New 
Drug, Antibiotic, and Biological Drug Product Regulations; Accelerated Approval (57 FR 13234, April 15, 1992). 
6 Part 312, subpart I. 
7 21 CFR 312.300(b)(1). 
  2 
 
  Contains Nonbinding Recommendations 
 
  Note: For the purposes of this guidance, the terms condition, disease, and illness are used 
interchangeably.  All conditions meeting the definition of life-threatening as set forth at 
 312.81(a) would also be serious conditions. 
 
2.  Whether the Drug Is Intended to Treat a Serious Condition 
 
As referenced in section IV, the statutory and regulatory eligibility criteria for expedited 
programs require that a drug be intended to treat a serious condition.  To satisfy this criterion, a 
drug must be intended to have an effect on a serious condition or a serious aspect of a condition, 
such as a direct effect on a serious manifestation or symptom of a condition or other intended 
effects, including the following:  
 
  A diagnostic product intended to improve diagnosis or detection of a serious condition in 
a way that would lead to improved outcomes 
 
  A product intended to mitigate or prevent a serious treatment-related side effect (e.g., 
serious infections in patients receiving immunosuppressive therapy) 
 
  A product intended to avoid or diminish a serious adverse event associated with available 
therapy for a serious condition (e.g., product that is less cardiotoxic than available cancer 
therapy)8 
 
  A product intended to prevent a serious condition or reduce the likelihood that the 
condition will progress to a more serious condition or a more advanced stage of disease 
 
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 drug9 and 
 
  Is relevant to current U.S. standard of care (SOC) for the indication 
 
 
8 Sponsors considering an expedited drug development designation or program for a drug intended to avoid a serious 
adverse event associated with available therapy or diminish its severity should be aware that they will need to 
provide data that directly support the effect corresponding to the level of evidence needed to meet the qualifying 
criteria for the relevant designation or program (e.g., phase 3 data demonstrating lower incidence or severity of the 
serious adverse reaction compared to available therapy for priority review).  The requisite data may be very difficult 
to obtain in early development, particularly for purposes of breakthrough therapy designation.   
9 There may be a substantial number of approved therapies with varying relevance to how a serious disease is 
currently treated in the United States, including therapies that are no longer used or are used rarely.  Only in 
exceptional cases will a treatment that is not approved for the indicated use or is not FDA-regulated (e.g., surgery) 
be considered available therapy.  In those cases, FDA may consider an unapproved or unlicensed therapy to 
constitute available therapy if the safety and effectiveness of the use is supported by compelling evidence, including 
extensive evidence in the published literature (e.g., certain well-established oncologic treatments).   
  3 
 
  Contains Nonbinding Recommendations 
 
FDAs available therapy determination generally focuses on treatment options that reflect the 
current SOC for the specific indication (including the disease stage) for which a product is being 
developed.  In evaluating the current SOC, FDA considers recommendations by authoritative 
scientific bodies (e.g., National Comprehensive Cancer Network, American Academy of 
Neurology) based on clinical evidence and other reliable information that reflects current clinical 
practice.  When a drug development program targets a subset of a broader disease population 
(e.g., a subset identified by a genetic mutation), the SOC for the broader population, if there is 
one, generally is considered available therapy for the subset, unless there is evidence that the 
SOC is less effective in the subset.   
 
Over the course of new drug development, it is foreseeable that the SOC for a given condition 
may evolve (e.g., because of approval of a new therapy or new information about available 
therapies).  FDA will determine what constitutes available therapy at the time of the relevant 
regulatory decision for each expedited program a sponsor intends to use (e.g., generally early in 
development for fast track and breakthrough therapy designations, at time of biologics license 
application (BLA) or new drug application (NDA) submissions for priority review designation, 
during BLA or NDA review for accelerated approval).  FDA encourages sponsors to discuss 
available therapy considerations with the Agency during interactions with FDA.       
 
As appropriate, FDA may consult with special Government employees or other experts when 
making an available therapy determination. 
 
When determining whether a drug granted accelerated approval or approved with a risk 
evaluation and mitigation strategy (REMS) that includes elements to assure safe use (ETASU) 
under section 505-1 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355-
1), is considered available therapy, the following principles will be applied: 
 
  A drug would not be considered available therapy if the drug is granted accelerated 
approval based on a surrogate endpoint or an intermediate clinical endpoint and clinical 
benefit has not been verified by postapproval studies.  (See section III.C.3.) 
 
  A drug would be considered available therapy if the drug is granted accelerated approval 
because of restricted distribution and the study population for the new drug under 
development is eligible to receive the approved drug under the restricted distribution 
program.  Similarly, a drug would be considered available therapy if the study population 
for the new drug under development is eligible to receive the approved drug under the 
ETASU REMS. 
 
C.  Unmet Medical Need 
 
An unmet medical need is a condition whose treatment or diagnosis is not addressed 
adequately by available therapy.  An unmet medical need includes an immediate need 
for a defined population (i.e., to treat a serious condition with no or limited treatment) or 
a longer-term need for society (e.g., to address the development of resistance to 
antibacterial drugs).   
 
  4 
 
  Contains Nonbinding Recommendations 
 
1.  Where There Is No Available Therapy  
 
If there is no available therapy for a serious condition, there is clearly an unmet medical need. 
 
2.  Where There Is Available Therapy  
 
When available therapy exists for a condition, a new treatment generally would be considered to 
address an unmet medical need if the treatment: 
 
  Has an effect on a serious outcome of the condition that is not known to be influenced by 
available therapy (e.g., progressive disability or disease progression when the available 
therapy has shown an effect on symptoms, but has not shown an effect on progressive 
disability or disease progression) 
 
  Has an improved effect on a serious outcome(s) of the condition compared with available 
therapy (e.g., superiority of the new drug to available therapy when either used alone or 
in combination with available therapy (i.e., as demonstrated in an add-on study)) 
 
  Has an effect on a serious outcome of the condition in patients who are unable to tolerate 
or failed to respond to available therapy  
 
  Can be used effectively with other critical agents that cannot be combined with available 
therapy 
 
  Provides efficacy comparable to those of available therapy, while (1) avoiding serious 
toxicity that occurs with available therapy, (2) avoiding less serious toxicity that is 
common and causes discontinuation of treatment of a serious condition, or (3) reducing 
the potential for harmful drug interactions 
 
  Provides safety and efficacy comparable to those of available therapy but has a 
documented benefit, such as improved compliance, that is expected to lead to an 
improvement in serious outcomes 
 
  Addresses an emerging or anticipated public health need, such as a drug shortage 
 
In some disease settings, a drug that is not shown to provide a direct efficacy or safety advantage 
over available therapy may nonetheless provide an advantage that would be of sufficient public 
health benefit to qualify as meeting an unmet medical need.  For example, in a condition for 
which there are approved therapies that have a modest response rate or significant heterogeneity 
in response, a drug with a novel mechanism of action (but comparable safety and effectiveness) 
could have the potential to provide an advantage over available therapy in some patients.  In such 
a case, the novel mechanism of action should have a well-understood relationship to the disease 
pathophysiology.  In addition, there should be a reasonable basis for concluding that a significant 
number of patients may respond differently to the new drug compared with available therapy.  
Thus, mechanistic diversity, even without a documented efficacy or safety advantage, could be 
advantageous in disease settings in which drugs become less effective or ineffective over time.  
  5 
 
  Contains Nonbinding Recommendations 
 
For example, infectious disease drugs or targeted cancer therapies with novel mechanisms of 
action, although appearing to have efficacy similar to available therapy across the disease 
population, could benefit patients who no longer respond to available therapy.  Accordingly, 
FDA intends to consider a range of potential advantages over available therapy beyond those 
shown in head-to-head comparisons.      
 
3.  Where the Only Available Therapy Was Approved Under the Accelerated 
Approval Program Based on a Surrogate Endpoint or an Intermediate Clinical 
Endpoint and Clinical Benefit Has Not Yet Been Verified 
 
As discussed in sections VII and III.B., FDA recognizes, as a general matter, that it is preferable 
to have more than one treatment approved under the accelerated approval provisions because of 
the possibility that clinical benefit may not be verified in postapproval confirmatory trials.  FDA 
will therefore consider products as addressing an unmet medical need if the only approved 
treatments were granted accelerated approval based on a surrogate endpoint or an intermediate 
clinical endpoint and clinical benefit has not been verified by postapproval studies.
  6 
 
  Contains Nonbinding Recommendations 
 
IV.  OVERVIEW OF EXPEDITED PROGRAMS 
 
The table provides an overview of the four expedited programs.  Additional details on the specific 
programs are found in the sections that follow.  Note that a drug development program may qualify 
for more than one expedited program. 
 
Comparison of FDAs Expedited Programs for Serious Conditions 
  Fast Track  Breakthrough  Accelerated Approval  Priority Review 
Therapy 
Nature of  Designation  Designation  Approval Pathway  Designation 
program 
Reference   Section 506(b) of the   Section 506(a) of the   21 CFR part 314, subpart H    Prescription Drug 
FD&C Act, as added  FD&C Act, as added   21 CFR part 601, subpart E   User Fee Act of 
by section 112 of the  by section 902 of   Section 506(c) of the FD&C  1992 
Food and Drug  FDASIA   
Act, as amended by section 
Administration 
901 of FDASIA  
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   A drug that is   A drug that treats a serious   An application 
criteria  intended to treat a  intended to treat a  condition AND generally  (original or 
serious condition  serious condition  provides a meaningful  efficacy 
AND nonclinical or  AND preliminary  advantage over available  supplement) for a 
clinical data  clinical evidence  therapies AND  drug that treats a 
demonstrate the  indicates that the drug  demonstrates an effect on a  serious condition 
potential to address  may demonstrate  surrogate endpoint that is  AND, if 
unmet medical need  substantial  reasonably likely to predict  approved, would 
OR  improvement on a  clinical benefit or on a  provide a 
 A drug that has been  clinically significant  clinical endpoint that can be  significant 
designated as a  endpoint(s) over  measured earlier than   improvement in 
qualified infectious  available therapies  irreversible morbidity or  safety or 
disease producta     mortality (IMM) that is  effectiveness OR 
  reasonably likely to predict   Any supplement 
an effect on IMM or other  that proposes a 
clinical benefit (i.e., an  labeling change 
intermediate clinical  pursuant to a 
endpoint)  report on a 
pediatric study 
under 505Ab OR 
 An application for 
a drug that has 
been designated 
as a qualified 
infectious disease 
productc  OR 
 Any application 
or supplement for 
a drug submitted 
with a priority 
review voucherd 
  7 
 
  Contains Nonbinding Recommendations 
 
Comparison of FDAs Expedited Programs for Serious Conditions 
  Fast Track  Breakthrough  Accelerated Approval  Priority Review 
Therapy 
Nature of  Designation  Designation  Approval Pathway  Designation 
program 
When to   With IND or after    With IND or after   The sponsor should   With original 
submit request   Ideally, no later than   Ideally, no later than  ordinarily discuss the  BLA, NDA, or 
the pre-BLA or pre- the end-of-phase 2  possibility of accelerated  efficacy 
NDA meeting  meeting  approval with the review  supplement 
division during 
development, supporting, 
for example, the use of the 
planned endpoint as a basis 
for approval and discussing 
the confirmatory trials, 
which should usually be 
already underway at the 
time of approval 
Timelines for   Within 60 calendar   Within 60 calendar   Not specified   Within 60 
FDA response  days of receipt of the  days of receipt of the  calendar days of 
request  request  receipt of original 
BLA, NDA, or 
efficacy 
supplement 
Features    Actions to expedite   Intensive guidance on   Approval based on an effect   Shorter clock for 
development and  efficient drug  on a surrogate endpoint or  review of 
review  development  an intermediate clinical  marketing 
 Rolling review    Organizational  endpoint that is reasonably  application (6 
  commitment  likely to predict a drugs  months compared 
 Rolling review  clinical benefit  with the 10-month 
standard review)e 
 Other actions to 
expedite review 
Additional   Designation may be   Designation may be   Promotional materials   Designation will 
considerations  rescinded if it no  rescinded if it no   Confirmatory trials to verify  be assigned at the 
longer meets the  longer meets the  and describe the anticipated   time of original 
qualifying criteria for  qualifying criteria for  effect on IMM or other  BLA, NDA, or 
fast trackf  breakthrough therapyg  clinical benefit  efficacy 
 Subject to expedited  supplement filing 
withdrawal  
a Title VIII of FDASIA, Generating Antibiotic Incentives Now (GAIN), provides incentives for the development of antibacterial and 
antifungal drugs for human use intended to treat serious and life threatening infections.  Under GAIN, a drug may be designated as a 
qualified infectious disease product (QIDP) if it meets the criteria outlined in the statute.  A drug that receives QIDP designation is eligible 
under the statute for fast track designation and priority review.  However, QIDP designation is beyond the scope of this guidance.   
b Any supplement to an application under section 505 of the FD&C Act that proposes a labeling change pursuant to a report on a pediatric 
study under this section shall be considered a priority review supplement per section 505A of the FD&C Act as amended by section 5(b) of 
the Best Pharmaceuticals for Children Act.   
c See footnote a above. 
d Any application or supplement that is submitted with a priority review voucher will be assigned a priority review.  Priority review 
vouchers will be granted to applicants of applications for drugs for the treatment or prevention of certain tropical diseases, as defined in 
section 524(a)(3) and (a)(4) of the FD&C Act and for treatment of rare pediatric diseases as defined in section 529(a)(3) of the FD&C Act.  
e As part of its commitments in PDUFA V, FDA has established a review model, the Program.  The Program applies to all new molecular 
entity NDAs and original BLAs, including applications that are resubmitted following a Refuse-to-File action, received from October 1, 
2012, through September 30, 2017.  For applications filed by FDA under the Program, the PDUFA review clock will begin at the 
conclusion of the 60 calendar day filing review period that begins on the date of FDA receipt of the original submission.     
f A sponsor may also withdraw fast track designation if the designation is no longer supported by emerging data or the drug development 
program is no longer being pursued (see section A.5. of Appendix 1). 
g A sponsor may also withdraw breakthrough therapy designation if the designation is no longer supported by emerging data or the drug 
development program is no longer being pursued (see section B.5. of Appendix 1). 
  8 
 
  Contains Nonbinding Recommendations 
 
V.  FAST TRACK DESIGNATION 
 
Section 506(b) of the FD&C Act provides for the designation of a drug as a fast track product    
. . . if it is intended, whether alone or in combination with one or more other drugs, for the 
treatment of a serious or life-threatening disease or condition, and it demonstrates the potential to 
address unmet medical needs for such a disease or condition.   This provision is intended to 
facilitate development and expedite review of drugs to treat serious and life-threatening 
conditions so that an approved product can reach the market expeditiously.  This section 
describes the qualifying criteria and the features of fast track designation.  Appendix 1 describes 
the process for fast track designation.   
 
A.  Qualifying Criteria for Fast Track Designation 
 
Fast track designation applies to the drug (either alone or in combination with other drugs) and 
the specific use for which it is being studied.  The term drug refers to the combination of two or 
more drugs if the combination is the subject of the fast track designation or request.  Where 
appropriate, FDA may grant designation to the development of a new use of an approved drug.  
 
1.  Serious Condition 
 
See section III.A. 
 
2.  Demonstrating the Potential to Address Unmet Medical Need  
 
The type of information needed to demonstrate the potential of a drug to address an unmet 
medical need will depend on the stage of drug development at which fast track designation is 
requested.  Early in development, evidence of activity in a nonclinical model, a mechanistic 
rationale, or pharmacologic data could be used to demonstrate such potential.  Later in 
development, available clinical data should demonstrate the potential to address an unmet 
medical need.  See section III.C. 
 
B.  Features of Fast Track Designation 
 
1.  Actions to Expedite Development and Review  
 
There are opportunities for frequent interactions with the review team for a fast track product.  
These include meetings with FDA, including pre-IND meetings, end-of-phase 1 meetings, and 
end-of-phase 2 meetings to discuss study design, extent of safety data required to support 
approval, dose-response concerns, and use of biomarkers.  Other meetings may be scheduled as 
appropriate (e.g., to discuss accelerated approval, the structure and content of an NDA, and other 
critical issues).   
 
In addition, such a product could be eligible for priority review if supported by clinical data at 
the time of BLA, NDA, or efficacy supplement submission (see section VIII). 
 
  9 
 
  Contains Nonbinding Recommendations 
 
2.  Submission of Portions of an Application (Rolling Review) 
 
If FDA determines, after preliminary evaluation of clinical data submitted by a sponsor, that a 
fast track product may be effective, the Agency may consider reviewing portions of a 
marketing application before the sponsor submits the complete application (see Appendix 
2).10 
 
VI.  BREAKTHROUGH THERAPY DESIGNATION 
 
Section 506(a) of the FD&C Act provides for designation of a drug as a breakthrough therapy    
. . . if the drug is intended, alone or in combination with 1 or more other drugs, to treat a serious 
or life-threatening disease or condition and preliminary clinical evidence indicates that the drug 
may demonstrate substantial improvement over existing therapies on 1 or more clinically 
significant endpoints, such as substantial treatment effects observed early in clinical 
development.  It is important to recognize that the standard for breakthrough therapy 
designation is not the same as the standard for drug approval.  The clinical evidence needed to 
support breakthrough designation is preliminary.  In contrast, as is the case for all drugs, FDA 
will review the full data submitted to support approval of drugs designated as breakthrough 
therapies to determine whether the drugs are safe and effective for their intended use before they 
are approved for marketing.  This section describes the qualifying criteria and the features of 
breakthrough therapy designation.  Appendix 1 describes the process for breakthrough therapy 
designation. 
 
Not all products designated as breakthrough therapies ultimately will be shown to have the 
substantial improvement over available therapies suggested by the preliminary clinical evidence 
at the time of designation.  If the designation is no longer supported by subsequent data, FDA 
may rescind the designation.11  Because FDA commits significant resources to work particularly 
closely with sponsors of breakthrough therapy products, the Agency needs to focus its resources 
on breakthrough therapy drug development programs that continue to meet the programs 
qualifying criteria (see section B.5. in Appendix 1).   
 
A.  Qualifying Criteria for Breakthrough Therapy Designation 
 
Breakthrough therapy designation applies to the drug (either alone or in combination with other 
drugs) and the specific use for which it is being studied.  The term drug refers to the combination 
of two or more drugs if the combination is the subject of the breakthrough therapy designation or 
request.  Where appropriate, FDA may grant designation to the development of a new use of an 
approved drug. 
 
1.  Serious Condition 
 
See section III.A. 
 
 
10 Section 506(d)(1) of the FD&C Act. 
11 After the sponsor completes the development program, the product may still have sufficient evidence to support 
marketing approval. 
  10 
 
  Contains Nonbinding Recommendations 
 
2.  Existing (or Available) Therapies 
 
See section III.B. 
 
3.  Preliminary Clinical Evidence 
 
Unlike the information that could support fast track designation, which could include theoretical 
rationale, mechanistic rationale (based on nonclinical data), or evidence of nonclinical activity, 
breakthrough therapy designation requires preliminary clinical evidence of a treatment effect that 
may represent substantial improvement over available therapies for the treatment of a serious 
condition.  For purposes of breakthrough therapy designation, preliminary clinical evidence 
means evidence that is sufficient to indicate that the drug may demonstrate substantial 
improvement in effectiveness or safety over available therapies, but in most cases is not 
sufficient to establish safety and effectiveness for purposes of approval.  FDA expects that such 
evidence generally would be derived from phase 1 or 2 trials.  Nonclinical information could 
support the clinical evidence of drug activity.  In all cases, preliminary clinical evidence 
demonstrating that the drug may represent a substantial improvement over available therapy 
should involve a sufficient number of patients to be considered credible.  However, FDA 
recognizes that the data cannot be expected to be definitive at the time of designation.   
 
Ideally, preliminary clinical evidence indicating a substantial improvement over available 
therapies would be derived from a study that compares the investigational drug to an available 
therapy (or placebo, if there is no available therapy) in clinical testing or from a study that 
compares the new treatment plus SOC to the SOC alone.  FDA encourages sponsors to obtain 
some preliminary comparative data of this type early in development.  Other types of clinical 
data that also could be persuasive include single-arm studies comparing the new treatment with 
well-documented historical experience.  Generally, FDA expects that such historically controlled 
data would be persuasive only if there is a large difference between the new treatment and 
historical experience.  For example, where lung function decline is a major manifestation of a 
disease, single-arm study data showing that a new drug significantly increases lung function 
could be persuasive if there is no available therapy that increases lung function.  Data 
demonstrating that a cancer drug substantially increases overall response rate compared with 
historical controls (e.g., historical response rate with available therapy), with consideration of 
duration of the response, also could be persuasive.  Sponsors contemplating the use of historical 
controls should consult FDAs ICH guidance for industry E10 Choice of Control Group and 
Related Issues in Clinical Trials for more-detailed discussions.12 
   
4.  May Demonstrate Substantial Improvement on Clinically Significant Endpoint(s) 
 
 
12 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
Drugs guidance Web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm and the Biologics 
guidance Web page at 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
  11 
 
  Contains Nonbinding Recommendations 
 
To support a breakthrough therapy designation, the preliminary clinical evidence must show that 
the drug may demonstrate substantial improvement over available therapy on one or more 
clinically significant endpoints.   
 
Substantial Improvement:  The determination of whether the improvement over available therapy 
is substantial is a matter of judgment and depends on both the magnitude of the drugs effect on a 
clinically significant endpoint (which could include duration of the effect) and the importance of 
the observed effect to the treatment of the serious condition or serious aspect of the condition.  In 
general, the preliminary clinical evidence should show a clear advantage over available therapy.   
 
Approaches to demonstrating substantial improvement include the following: 
 
  Direct comparison of the new drug to available therapy shows a much greater or more 
important response (e.g., complete responses where the control treatment generally 
results only in partial responses).  Such a trial could be conducted in treatment-naive 
patients or in those whose disease failed to respond to available therapies, either as a 
comparison with the failed therapy (if ethically acceptable) or as a no-treatment 
controlled study. 
 
  If there is no available therapy, the new drug shows a substantial and clinically 
meaningful effect on an important outcome when compared with a placebo or a well-
documented historical control. 
 
  The new drug added to available therapy results in a much greater or more important 
response compared to available therapy in a controlled study or to a well-documented 
historical control.  This trial also could be conducted in treatment-naive patients or in 
those whose disease failed to respond to available therapies.   
 
  The new drug has a substantial and clinically meaningful effect on the underlying cause 
of the disease, in contrast to available therapies that treat only symptoms of the disease, 
and preliminary clinical evidence indicates that the drug is likely to have a disease-
modifying effect in the long term (e.g., a sustained clinical benefit compared with a 
temporary clinical benefit provided by available therapies).  
 
  The new drug reverses or inhibits disease progression, in contrast to available therapies 
that only provide symptomatic improvement. 
 
  The new drug has an important safety advantage that relates to serious adverse reactions 
(e.g., those that may result in treatment interruption) compared with available therapies 
and has similar efficacy. 
 
Clinically Significant Endpoint:  For purposes of breakthrough therapy designation, FDA 
considers clinically significant endpoint generally to refer to an endpoint that measures an effect 
on irreversible morbidity or mortality (IMM) or on symptoms that represent serious 
consequences of the disease.  It can also refer to findings that suggest an effect on IMM or 
serious symptoms, including: 
  12 
 
  Contains Nonbinding Recommendations 
 
 
  An effect on an established surrogate endpoint that typically would be used to support 
traditional approval 
 
  An effect on a surrogate endpoint or intermediate clinical endpoint (see section VII.B.2.) 
considered reasonably likely to predict a clinical benefit (i.e., the accelerated approval 
standard) 
 
  A significantly improved safety profile compared with available therapy (e.g., less dose-
limiting toxicity for an oncology agent), with evidence of similar efficacy   
 
In a breakthrough therapy designation request, a sponsor should provide justification for why the 
endpoint or other findings should be considered clinically significant. 
 
In rare cases, a pharmacodynamic (PD) biomarker may be considered a clinically significant 
endpoint if it strongly suggests the potential for a clinically meaningful effect on the underlying 
disease.  In such cases, a sponsor should provide evidence supporting the use of the PD 
biomarker.  Such evidence should include, for example, (1) the extent of understanding of the 
disease pathophysiology, (2) whether the biomarker is on a causal pathway of the disease 
process, and (3) the time course of the drugs effect on the biomarker (e.g., the biomarker can be 
measured earlier than a surrogate endpoint used for accelerated approval).  In addition, strong 
evidence of the drugs effect on the PD biomarker generally is expected.  FDA is more likely to 
rely on a PD biomarker for breakthrough therapy designation in a disease setting in which there 
is no available therapy, if the evidence supports such use.   
   
B.  Features of Breakthrough Therapy Designation 
 
1.  Intensive Guidance on an Efficient Drug Development Program, Beginning as 
Early as Phase 1 
 
As discussed previously, breakthrough therapy designation will usually mean that the effect of 
the drug will be large compared with available therapies.  In such cases, the development 
program for the breakthrough therapy could be considerably shorter than for other drugs 
intended to treat the disease being studied.  However, FDA notes that a compressed drug 
development program still must generate adequate data to demonstrate that the drug is safe and 
effective to meet the statutory standard for approval.13  Omitting components of the drug 
development program that are necessary for such a determination can significantly delay, or even 
preclude, marketing approval. 
 
Sponsors can design efficient clinical trials in a number of ways.  FDA will seek to ensure that a 
sponsor of a product designated as a breakthrough therapy receives timely advice and interactive 
communications to help the sponsor design and conduct a drug development program as 
 
13 Section 505(d) of the FD&C Act and section 351(a) of the Public Health Service Act.  
  13 
 
  Contains Nonbinding Recommendations 
 
efficiently as possible.14  During these interactions, the Agency may suggest, or a sponsor may 
propose, alternative clinical trial designs (e.g., adaptive designs, an enrichment strategy, 
crossover or N-of-1 design, use of historical controls) or use of an interim analysis by a data 
monitoring committee.15  These trial designs may result in smaller trials or more efficient trials 
that require less time to complete and may help minimize the number of patients exposed to a 
potentially less efficacious treatment (i.e., the control group treated with available therapy).  
Such approaches may be especially useful in studies in rare diseases.  For example, single-arm 
trials may be an important option in rare diseases with well-understood pathophysiology and a 
well-defined disease course. 
 
FDA anticipates that the review team and the sponsor will meet and interact throughout drug 
development to address these and other important issues at different phases of development.  In 
addition, a sponsor should be prepared for a more rapid pace for other aspects of the drug 
development (e.g., manufacturing (see section IX.A.), development of a necessary companion 
diagnostic (see section IX.D.)). 
 
2.  Organizational Commitment Involving Senior Managers 
 
FDA intends to expedite the development and review of a breakthrough therapy by intensively 
involving senior managers and experienced review and regulatory health project management 
staff in a proactive, collaborative, cross-disciplinary review.  Where appropriate, FDA also 
intends to assign a cross-disciplinary project lead for the review team to facilitate an efficient 
review of the drug development program.  The cross-disciplinary project lead will serve as a 
scientific liaison between members of the review team (e.g., medical; clinical pharmacology; 
pharmacology-toxicology; chemistry, manufacturing, and controls (CMC); compliance; 
biostatistics), facilitating coordinated internal interactions and communications with a sponsor 
through the review divisions regulatory health project manager. 
 
3.  Submission of Portions of an Application (Rolling Review) 
 
FDA has determined that it is appropriate for a drug designated as a breakthrough therapy to be 
able to obtain rolling review.  Therefore, if FDA determines, after preliminary evaluation of 
clinical data submitted by the sponsor, that a breakthrough therapy product may be effective, the 
Agency may consider reviewing portions of a marketing application before the sponsor submits 
the complete application (see Appendix 2).  
 
4.  Other Actions to Expedite Review 
 
 
14 As noted in IX. GENERAL CONSIDERATIONS, it is important that sponsors respond promptly to FDA 
inquiries, which may include, for example, requests for information on various aspects of the drug development 
program. 
15 For more discussion of alternative clinical trial designs, see the draft guidance for industry Adaptive Design 
Clinical Trials for Drugs and Biologics and the draft guidance for industry Enrichment Strategies for Clinical Trials 
to Support Approval of Human Drugs and Biological Products.  When final, these guidances will represent FDAs 
current thinking on these topics.  See also the ICH E10 and the guidance for clinical trial sponsors Establishment 
and Operation of Clinical Trial Data Monitoring Committees. 
  14 
 
  Contains Nonbinding Recommendations 
 
In addition, such a product could be eligible for priority review if supported by clinical data at 
the time of BLA, NDA, or efficacy supplement submission. 
 
VII.  ACCELERATED APPROVAL 
 
The accelerated approval provisions of FDASIA in section 506(c) of the FD&C Act provide that 
FDA may grant accelerated approval to: 
 
. . . a product for a serious or life-threatening disease or condition . . . upon a 
determination that the product has an effect on a surrogate endpoint that is reasonably 
likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier 
than irreversible morbidity or mortality, that is reasonably likely to predict an effect on 
irreversible morbidity or mortality or other clinical benefit, taking into account the 
severity, rarity, or prevalence of the condition and the availability or lack of alternative 
treatments. 
 
For drugs granted accelerated approval, postmarketing confirmatory trials have been required to 
verify and describe the anticipated effect on IMM or other clinical benefit (see sections VII.D.2. 
and VII.D.3.).16   
 
This section describes the qualifying criteria, relevant terms, and the conditions of accelerated 
approval.  The provisions of FDASIA facilitate somewhat broader use of accelerated approval to 
expedite patients access to important treatments for serious conditions.  FDA believes the new 
provisions provide additional flexibility concerning the implications of available therapy on 
eligibility for accelerated approval (see section VII.A.2.).  They also provide clarification 
concerning the use of clinical endpoints (herein referred to as intermediate clinical endpoints) as 
a basis for accelerated approval (see section VII.B.2.).  In addition, the new provisions make 
clear that FDA has the authority to consider pharmacologic or other evidence developed using 
biomarkers or other scientific methods or tools, in conjunction with other data, in determining 
whether an endpoint is reasonably likely to predict clinical benefit (see section VII.C.).17  By 
indicating that FDA should take into account, . . . the severity, rarity, or prevalence of the 
condition . . . in considering whether to grant accelerated approval, FDASIA reinforces the 
Agencys longstanding commitment to regulatory flexibility regarding the evidence required to 
support product approval for the treatment of serious or life-threatening diseases with limited 
therapeutic options. 
 
The accelerated approval pathway has been used primarily in settings in which the disease course 
is long and an extended period of time would be required to measure the intended clinical benefit 
of a drug.  For example, accelerated approval has been used extensively in the approval of drugs 
to treat a variety of cancers and human immunodeficiency virus (HIV) disease where an effect 
 
16 Section 506(c)(2)(A) of the FD&C Act.  
17 Section 506(c)(1)(B) of the FD&C Act.  21 CFR 314.510 and 601.41 provide that the Agency may consider . . . 
epidemiologic, therapeutic, pathophysiologic, or other evidence . . . in determining whether an endpoint is 
reasonably likely to predict clinical benefit.  FDASIA provides that FDA may consider . . . epidemiological, 
pathophysiological, therapeutic, pharmacologic, or other evidence developed using biomarkers, for example, or 
other scientific methods or tools.   
  15 
 
  Contains Nonbinding Recommendations 
 
on tumor growth or viral load can be assessed rapidly, but demonstrating an effect on survival or 
morbidity generally requires lengthy and sometimes large trials because of the duration of the 
typical disease course.  Accelerated approval is also potentially useful in acute disease settings 
where the intended clinical benefit can be demonstrated only in a very large study because the 
clinical event that would need to be evaluated to demonstrate clinical benefit occurs rarely.  For 
example, accelerated approval could be used for an acute condition where an effect on a 
surrogate endpoint could be shown in a small number of patients, but a much larger study would 
be needed to show the effect on a clinical outcome, such as survival.  
 
FDA encourages sponsors to communicate with the Agency early in development concerning the 
potential eligibility of a drug for accelerated approval, proposed surrogate endpoints or 
intermediate clinical endpoints, clinical trial designs, and planning and conduct of confirmatory 
trials.  A sponsor seeking accelerated approval may also need to prepare for a more rapid pace 
for other aspects of the drug development (e.g., manufacturing (see section IX.A.),  development 
of a necessary companion diagnostic (see section IX.D.)). 
 
A.  Qualifying Criteria for Accelerated Approval 
 
At the time a product is granted accelerated approval, FDA has determined that an effect on the 
endpoint used to support approvala surrogate endpoint or an intermediate clinical endpointis 
reasonably likely to predict clinical benefit.  The principal risk of this approach is the possibility 
that patients will be exposed to a drug that ultimately will not be shown to provide an actual 
clinical benefit.  In addition, there generally will be fewer, smaller, or shorter clinical trials than 
is typical for a drug receiving traditional approval, which may generally mean there is less 
information about the occurrence of rare or delayed adverse events.  Uncertainty about whether 
clinical benefit will be verified and the possibility of undiscovered risks are the primary reasons 
that accelerated approval is reserved for drugs intended to treat a serious condition and that 
appear to provide a meaningful advantage over available therapy.   
 
1.  Serious Condition 
 
See section III.A. 
 
2.  Meaningful Advantage Over Available Therapy 
 
The accelerated approval regulations state that accelerated approval is available only for drugs 
that provide a meaningful therapeutic benefit over existing treatments.18  The accelerated 
approval provisions of section 901 of FDASIA (amending section 506 of the FD&C Act) require 
FDA to . . .tak[e] into account . . . the availability or lack of alternative treatments.   
 
Amended section 506(c) clarifies the Agencys flexibility in administering the accelerated 
approval program.  For example, an alternative therapy with efficacy comparable to available 
therapy, but with a different mechanism of action, could be of added clinical value in a disease 
setting in which a significant number of patients may respond differently to the new therapy.  
The discussion of unmet medical need in section III.C.2. provides examples of situations in 
 
18 21 CFR 314.500 and 601.40. 
  16 
 
  Contains Nonbinding Recommendations 
 
which a drug could be shown to provide a meaningful advantage over available therapy, 
including some in which there may not be a demonstrated direct efficacy or safety advantage.  
Section III.B. describes what constitutes available therapy when determining whether a drug 
provides a meaningful advantage. 
   
3.  Demonstrates an Effect on an Endpoint That Is Reasonably Likely to Predict 
Clinical Benefit 
 
These endpoints are discussed in section VII.B.  The basis for determining whether an endpoint 
is reasonably likely to predict clinical benefit is discussed in section VII.C. 
 
B.  Accelerated Approval Endpoints 
 
The two types of endpoints that can be used as a basis for accelerated approval are:  (1) a 
surrogate endpoint that is considered reasonably likely to predict clinical benefit and (2) a 
clinical endpoint that can be measured earlier than IMM that is reasonably likely to predict an 
effect on IMM or other clinical benefit (also see section VII.D.2.).  For purposes of this 
guidance, these categories of endpoints are referred to as surrogate endpoints and intermediate 
clinical endpoints, respectively.   
 
A clinical endpoint is a characteristic or variable that directly measures a therapeutic effect of a 
drugan 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 treatments risks to determine 
whether there is an overall benefit for patients (i.e., a positive benefit-risk profile). 
 
1.  Surrogate Endpoints  
 
For purposes of accelerated approval, a surrogate endpoint is a marker, such as a laboratory 
measurement, radiographic image, physical sign, or other measure, that is thought to predict 
clinical benefit, but is not itself a measure of clinical benefit.  Depending on the strength of the 
evidence supporting the ability of a marker to predict clinical benefit, the marker may be a 
surrogate endpoint that is known to predict clinical benefit (a validated surrogate endpoint that 
could be used for traditional approval), a surrogate endpoint that is reasonably likely to predict a 
drugs intended clinical benefit (and that could therefore be used as a basis for accelerated 
approval), or a marker for which there is insufficient evidence to support reliance on the marker 
as either kind of surrogate endpoint (and that therefore cannot be used to support traditional or 
accelerated approval of a marketing application).   
 
Examples of surrogate endpoints that FDA has used to support accelerated approval include the 
following: 
 
  Prolonged suppression of HIV viral load in plasma has been shown to reduce the 
morbidity and mortality associated with HIV disease and has been the basis for 
  17 
 
  Contains Nonbinding Recommendations 
 
traditional approval.  Shorter-term suppression of viral load has been used in the past as a 
surrogate to support accelerated approval because it was considered reasonably likely to 
predict an effect on morbidity or mortality.  Data now demonstrate that short-term 
suppression of viral load may support full approval, in some circumstances.19 
 
  Clearance of bacteria from the blood stream as evidenced by a laboratory measurement of 
bacteria in the blood has been considered reasonably likely to predict the clinical 
resolution of infection. 
 
  Outcomes of 6-month follow-up treatment (i.e., sputum culture status and infection 
relapse rate) have been considered reasonably likely to predict the resolution of 
pulmonary tuberculosis. 
 
  Decrease in iron stores for patients with iron overload caused by thalassemia has been 
considered reasonably likely to predict a decrease in transfusion-related adverse events 
caused by iron overload in the body. 
 
  Radiographic evidence of tumor shrinkage (response rate) in certain cancer types has 
been considered reasonably likely to predict an improvement in overall survival. 
 
2.  Intermediate Clinical Endpoints  
 
For purposes of accelerated approval, an intermediate clinical endpoint is a measurement of a 
therapeutic effect that can be measured earlier than an effect on IMM and is considered 
reasonably likely to predict the drugs effect on IMM or other clinical benefit.  An important 
question is whether the demonstrated therapeutic effect alone would be a basis for traditional 
approval.  Approvals for products for serious conditions based on clinical endpoints other than 
IMM will usually be considered under traditional approval procedures.  Approvals based on such 
clinical endpoints will be considered under the accelerated approval pathway only when it is 
essential to determine effects on IMM or other clinical benefit in order to confirm the predicted 
clinical benefit that led to approval. Although FDA has limited experience with accelerated 
approvals based on intermediate clinical endpoints, FDA believes intermediate clinical endpoints 
generally could be used to support accelerated approval in situations such as: 
 
  A study demonstrates a relatively short-term clinical benefit in a chronic disease setting 
in which assessing durability of the clinical benefit is essential for traditional approval, 
but the short-term benefit is considered reasonably likely to predict long-term benefit. 
 
  A clinical endpoint demonstrates a clinical benefit that is reasonably likely to predict an 
effect on IMM in a disease setting in which it is essential to confirm the effect on IMM 
(e.g., because available therapy has established effects on IMM). 
 
 
19 See the draft guidance for industry Human Immunodeficiency Virus-1 Infection: Developing Antiretroviral Drugs 
for Treatment.  When final, this guidance will represent FDA's current thinking on this topic.  
  18 
 
  Contains Nonbinding Recommendations 
 
Examples of cases in which FDA has used an intermediate clinical endpoint to support 
accelerated approval include the following: 
 
  A treatment for multiple sclerosis was approved based on a large therapeutic effect on 
relapse rate through approximately 13 months of treatment, but where there was 
uncertainty about the durability of the observed effect.  Under accelerated approval, the 
sponsor was required to continue the existing trials into the postmarketing period to 
confirm durability of the observed effect at 2 years.  
 
  A treatment for preterm labor was approved based on a demonstration of delay in 
delivery.  Under accelerated approval, the sponsor was required to conduct postmarketing 
studies to demonstrate improved long-term postnatal outcomes.  
 
FDA will not grant accelerated approval to products that meet standards for traditional approval.  
Sponsors considering a development program for accelerated approval based on an intermediate 
clinical endpoint should discuss their development program with the appropriate review division 
early in drug development.  
 
C.  Evidentiary Criteria for Accelerated Approval 
 
Drugs granted accelerated approval must meet the same statutory standards for safety and 
effectiveness as those granted traditional approval.20  For effectiveness, the standard is 
substantial evidence based on adequate and well-controlled clinical investigations.21  For safety, 
the standard is having sufficient information to determine whether the drug is safe for use under 
conditions prescribed, recommended, or suggested in the proposed labeling.22  Under accelerated 
approval, FDA can rely on a particular kind of evidence, such as a drugs effect on a surrogate 
endpoint, as a basis for approval.  FDA carefully evaluates such evidence to ensure that any 
remaining doubts about the relationship of the effect on the surrogate to clinical benefit are 
resolved by additional postapproval studies or trials.23  An application for accelerated approval 
should also include evidence that a proposed surrogate endpoint or an intermediate clinical 
endpoint is reasonably likely to predict the intended clinical benefit of a drug.   
 
Determining whether an endpoint is reasonably likely to predict clinical benefit is a matter of 
judgment that will depend on the biological plausibility of the relationship between the disease, 
the endpoint, and the desired effect and the empirical evidence to support that relationship.  The 
empirical evidence may include . . . epidemiological, pathophysiological, therapeutic, 
pharmacologic, or other evidence developed using biomarkers, for example, or other scientific 
methods or tools.24  Evidence of pharmacologic activity alone is not sufficient, however.25  
Clinical data should be provided to support a conclusion that a relationship of an effect on the 
 
20 Section 505(d) of the FD&C Act. 
21 Section 505(d)(5) of the FD&C Act. 
22 Section 505(d)(1) of the FD&C Act. 
23 57 FR 58942 at 58948. 
24 Section 506(c)(1)(B) of the FD&C Act. 
25 57 FR 58942. 
  19 
 
  Contains Nonbinding Recommendations 
 
surrogate endpoint or intermediate clinical endpoint to an effect on the clinical outcome is 
reasonably likely.  
 
In making the judgment as to whether a drugs effect on a given endpoint is reasonably likely to 
predict clinical benefit, FDA considers all relevant evidence and may consult external experts, as 
needed.  This guidance provides an overview of some of the important factors to consider in 
identifying and assessing the predictive potential of surrogate endpoints or intermediate clinical 
endpoints.  This guidance does not, however, address the specific clinical evidence needed to 
support a conclusion that a particular surrogate endpoint or intermediate clinical endpoint is 
reasonably likely to predict clinical benefit or IMM because such evidence is case-specific and is 
not readily generalizable.  
 
1.  Understanding of the Disease Process 
 
Surrogate endpoints are often thought to be a measure of the following, for example: 
  The underlying cause of the disease (e.g., elevated uric acid and gout, elevated blood 
pressure and hypertensive cardiovascular disease, low thyroxine levels and 
hypothyroidism, high ammonia levels and urea cycle disorders) 
 
  An effect that predicts the ultimate outcome (e.g., tumor shrinkage could be expected to 
delay symptomatic progression and improve survival, diuresis could be expected to 
improve symptoms of heart failure, effects on serum creatinine or glomerular filtration 
rate (if not transient or reversible) are accepted surrogates for predicting effects on 
chronic renal disease and delaying the occurrence of end-stage renal disease) 
 
  The state of the pathophysiologic pathway leading to the clinical outcome (e.g., low 
levels of the biomarker that increase with replacement of a missing enzyme or clotting 
factor) 
 
In such cases, the extent to which the pathophysiology of a disease is understood is an important 
factor in determining whether an endpoint is reasonably likely to predict clinical benefit.  If the 
disease process is complex, has multiple pathophysiologic or causal pathways, and is poorly 
understood, it may be difficult to determine whether an effect on a surrogate endpoint represents 
a meaningful effect on the causal pathway.  For example, for some reasonably well-understood 
enzyme deficiencies, replacement of the deficient enzyme reliably predicts clinical benefit.  In 
contrast, other enzyme deficiencies may involve a defect for which the pathophysiologic or 
causal pathways are not well understood and where enzyme replacement as measured by blood 
levels, but not tissue levels, will not reasonably predict the disease course or treatment results.  
 
Some effects on well-established, disease-related biomarkers26 may have little or no ability to 
predict clinical benefit or their ability to predict benefit may vary depending on the disease or the 
 
26 FDA's CDER has established the Biomarker Qualification Program to support work with external scientists and 
clinicians in developing biomarkers.  The Biomarker Qualification Program offers a formal process to guide 
submitters as they develop biomarkers and rigorously evaluate them for use in the regulatory process.  Details on the 
  20 
 
  Contains Nonbinding Recommendations 
 
intervention.  For example, in a patient with a fever caused by an infectious disease, a fall in a 
patients body temperature in response to a non-steroidal anti-inflammatory drug does not predict 
the drugs effect on the disease.  However, a fall in a patients body temperature in response to 
an antibiotic may be an indication of an effect on the disease.  Similarly, in prostate cancer, 
increased levels of prostate-specific antigen (PSA) may be the result of advancing tumor burden.  
Therefore, PSA may be correlated with the progression of prostate cancer and the risks of 
mortality.  However, the relationship between increasing PSA and disease progression and 
morbidity is not uniform.  Thus the ability of a drug to lower PSA levels cannot necessarily be 
relied upon to predict the drugs clinical benefit.    
 
2.  Understanding of the Relationship Between the Drugs Effect and the Disease 
Process 
 
The extent to which a drugs effect on the surrogate endpoint is known to predict an effect on the 
disease either because the effect is on the causal pathway or correlates with clinical outcomes is 
critical.  Sometimes this relationship can be assessed epidemiologically but it is most 
persuasively established by knowing that a drug that affects the surrogate endpoint also affects a 
clinical outcome.  Thus, lowering blood pressure has been shown repeatedly, with a wide variety 
of drugs, to reduce the incidence of stroke and cardiovascular disease in people with 
hypertension.  Similarly, killing infecting bacteria or viruses leads to curing infectious disease 
and shrinking a tumor for a sustained period can lead to improved survival in patients with some 
cancers.  These surrogate endpoint responses are thus understood to have positive effects on the 
disease process. 
 
Examples of factors to consider in identifying and assessing a surrogate endpoint thus include the 
following:   
  Whether there is reliable and consistent epidemiologic evidence supporting the 
relationship between the endpoint and the intended clinical benefit.27 
 
  How precisely the epidemiologic relationship between the endpoint and clinical outcome 
is defined.  For example, the extent to which an abnormal endpoint corresponds to a 
worse clinical outcome, as is the case for blood pressure and low-density lipoprotein 
(LDL) cholesterol.  (The stronger the correlation between the abnormality and clinical 
outcome, the stronger the basis for concluding that an effect on the endpoint would have 
a reasonably well-defined effect on the clinical outcome.) 
 
  Whether the effect on the surrogate endpoint has been shown to predict a clinical benefit 
with another drug or drugs.  This factor would generally be more persuasive if the drug is 
in the same or a closely related pharmacological class. 
 
program are available at 
http://www.fda.gov/drugs/developmentapprovalprocess/drugdevelopmenttoolsqualificationprogram/ 
ucm284076.htm. 
27 Note, however, that such a relationship does not always predict a favorable effect, as illustrated by failure of drugs 
that effectively lower premature ventricular beat rates or raise high-density lipoprotein (HDL) cholesterol to have 
the expected cardiovascular benefits.   
  21 
 
  Contains Nonbinding Recommendations 
 
 
Particularly in rare diseases, there may be limited information in the literature, lack of in-depth 
epidemiological or historical data, and little or no experience with other drugs to inform the 
interpretation of surrogate endpoints or intermediate clinical endpoints.  FDA may consult with 
external experts on surrogate endpoints and intermediate clinical endpoints where there is a lack 
of historical data for a given disease.28 
 
D.  Conditions of Accelerated Approval 
 
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.29  After 120 days following marketing approval, unless 
otherwise informed by the Agency, the applicant must submit promotional materials at least 30 
days prior to the intended time of initial dissemination of the labeling or initial publication of the 
advertisement.30 
 
2.  Confirmatory Trials 
 
For drugs granted accelerated approval, postmarketing confirmatory trials have been required to 
verify and describe the anticipated effect on IMM or other clinical benefit.  These trials must be 
completed with due diligence.31   
 
FDA has interpreted the due diligence requirement to mean that the postmarketing trial(s) 
intended to verify the clinical benefit must be conducted promptly to facilitate determination, as 
soon as possible, of whether clinical benefit has been verified.  The protocol for a postmarketing 
trial should be developed as early as possible, and timelines for the trial should be specified; for 
example, timelines for enrollment and trial completion should be stipulated.  There should be 
agreement between FDA and the sponsor on the design and conduct of the confirmatory trial(s). 
 
If it is clear during development that a product is intended to be approved under accelerated 
approval on the basis of a surrogate endpoint or an intermediate clinical endpoint, confirmatory 
trial(s) should be underway at the time the marketing application is submitted.  If it is not clear 
until shortly before or after submission of a marketing application that a surrogate endpoint or an 
intermediate clinical endpoint will be the proposed basis for accelerated approval, there should 
be agreement on the design and conduct of such trial(s) before approval.  
 
 
28 See, for example, section 569(a)(2), (b), and (c) of the FD&C Act, Consultation With External Experts on Rare 
Diseases, Targeted Therapies and Genetic Targeting of Treatments, which describes general consideration for 
consultation with external experts, topics for consultation, and classification as special Government employees.  
29 21 CFR 314.550 and 601.45.  
30 21 CFR 314.550 and 601.45. 
31 Section 506(c)(3)(A) of the FD&C Act and  314.510 and 601.41.  Where confirmatory trials verify clinical 
benefit, FDA generally will terminate the requirement (21 CFR 312.560 and 601.46). 
  22 
 
  Contains Nonbinding Recommendations 
 
Generally, the confirmatory trial would evaluate a clinical endpoint that directly measures 
clinical benefit.  For example, the confirmatory trial population would ordinarily be the same 
disease population that was studied to support accelerated approval.  In some cases, however, the 
commercial availability of a drug following accelerated approval may make it difficult to enroll 
patients in the same disease population.  In these cases, a confirmatory trial may be conducted in 
a different but related population that is capable of verifying the predicted clinical benefit.  This 
is often the case in oncology, where after accelerated approval of a drug for late-stage disease is 
granted, the confirmatory trial is conducted in an earlier stage of the same cancer. 
 
There are also cases in which additional evaluation (longer duration) of the same surrogate 
endpoint that was used to support accelerated approval (rather than a clinical endpoint) in the 
same population could be persuasive evidence of clinical benefit.  For example, in the case of 
HIV treatment, an effect on viral load of relatively short duration (24 weeks) was considered 
reasonably likely to predict clinical benefit supporting accelerated approval.  An effect of longer 
(1 year) viral load suppression was more convincingly related to durable clinical benefit in the 
setting of lifelong therapy and thus was used to verify clinical benefit for traditional approval.32 
 
When it is possible to use a later effect in a trial to verify the effect seen earlier in the same trial 
that supported accelerated approval, the same clinical trial(s) can be used to support accelerated 
approval and verify and describe the clinical benefit.  In this case, the protocol and the statistical 
analysis plan should clearly account for an analysis of the surrogate endpoint data to provide 
support for accelerated approval, with continuation of the randomized trial(s) to obtain data on 
the clinical endpoint that will be the basis for verifying the clinical benefit.  When the same trial 
is used to support accelerated approval and verify clinical benefit, the data to verify the clinical 
benefit may be, in some cases, nearly complete by the time of accelerated approval. 
 
3.  Withdrawal of Accelerated Approval 
 
FDA may withdraw approval of a drug or indication approved under the accelerated approval 
pathway if,33 for example: 
 
  A trial required to verify the predicted clinical benefit of the product fails to verify such 
benefit.  
 
  Other evidence demonstrates that the product is not shown to be safe or effective under 
the conditions of use.  
 
  The applicant fails to conduct any required postapproval trial of the drug with due 
diligence.  
 
 
32 Although an effect on viral load changes of short duration had been used in the past as a surrogate endpoint to 
support accelerated approval, FDA now considers this endpoint acceptable, in some circumstances, to grant 
traditional approval based on years of experience with this endpoint. 
33 See section 506(c)(3) of the FD&C Act and  314.530(a) and 601.43(a).  Part 314, subpart E and part 601, 
subpart H describe additional grounds for withdrawal. 
  23 
 
  Contains Nonbinding Recommendations 
 
  The applicant disseminates false or misleading promotional materials relating to the 
product.   
 
Approval of a drug may be withdrawn if trials fail to verify clinical benefit or do not demonstrate 
sufficient clinical benefit to justify the risks associated with the drug (e.g., show a significantly 
smaller magnitude or duration of benefit than was anticipated based on the observed effect on the 
surrogate). 
 
If FDA determines there are grounds for withdrawal, the Agency may ask the applicant to 
request withdrawal of approval under  314.150(d) or notify the applicant of FDAs proposal to 
withdraw approval in a notice of opportunity for hearing (NOOH).  The NOOH generally will 
state the proposed grounds for withdrawal of approval.34  Upon receipt of an NOOH, an 
applicant has 15 days to file a written request for a hearing.  If an applicant does not request a 
hearing within 15 days, the applicant waives its opportunity for hearing.35  An applicant may 
also request the Agency to withdraw approval of an application approved under accelerated 
approval.36   
 
VIII.  PRIORITY REVIEW DESIGNATION 
 
An application for a drug will receive priority review designation if it is for a drug that treats a 
serious condition and, if approved, would provide a significant improvement in safety or 
effectiveness.  In addition, specific statutory provisions provide for priority review for various 
types of applications, described in section IV.  A priority designation is intended to direct overall 
attention and resources to the evaluation of such applications.  This section describes the 
qualifying criteria and the features of priority review designation.  Appendix 1 describes the 
process for priority review designation.   
 
A.  Qualifying Criteria for Priority Review Designation 
 
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 at the time of NDA, BLA, or efficacy supplement 
filing whether the proposed drug would be a significant improvement in the safety or 
effectiveness of the treatment, prevention, or diagnosis of a serious condition.  Significant 
improvement may be illustrated by the following examples:  
 
  Evidence of increased effectiveness in treatment, prevention, or diagnosis of a condition 
 
 
34 21 CFR 314.530(b) and 601.43(b). 
35 21 CFR 314.530(c)(1) and 601.43(c)(1). 
36 21 CFR 314.150(c) and 601.5(a). 
  24 
 
  Contains Nonbinding Recommendations 
 
  Elimination or substantial reduction of a treatment-limiting adverse reaction  
 
  Documented enhancement of patient compliance that is expected to lead to an 
improvement in serious outcomes 
 
  Evidence of safety and effectiveness in a new subpopulation   
 
Although such evidence can come from clinical trials comparing a marketed product with the 
investigational drug, a priority review designation can be based on other scientifically valid 
information.  Generally, if there is an available therapy (see section III.B.), sponsors should 
compare their investigational drug to the available therapy in clinical testing with an attempt to 
show superiority relating to either safety or effectiveness.  Alternatively, sponsors could show 
the drugs ability to effectively treat patients who are unable to tolerate, or whose disease failed 
to respond to, available therapy or show that the drug can be used effectively with other critical 
agents that cannot be combined with available therapy.  Although such showings would usually 
be based on randomized trials, other types of controls could also be persuasive, for example, 
historical controls.37 
 
B.  Features of Priority Review Designation 
 
A priority review designation means FDAs goal is to take action on the marketing application 
within 6 months of receipt (compared with 10 months under standard review).  The PDUFA 
review clock for applications filed by FDA under the Program is described in section IV. 
 
IX.  GENERAL CONSIDERATIONS 
 
Communication with the Agency is a critical aspect of expedited programs.  FDA will strive to 
provide a timely response to a sponsors inquiry regarding an expedited development program.  
It is equally critical that a sponsor respond promptly to FDAs inquiries.38  This applies to formal 
meetings and related inquiries, written correspondence, and other interactions.  In addition to the 
many types of formal meetings39 and correspondence the Agency offers to sponsors, additional 
considerations for sponsors of expedited programs are highlighted in this section. 
 
A.  Manufacturing and Product Quality Considerations 
 
The sponsor of a product that receives an expedited drug development designation may need to 
pursue a more rapid manufacturing development program to accommodate the accelerated pace 
of the clinical program.  The sponsors product quality and CMC teams should initiate early 
 
37 Sponsors contemplating the use of historical controls should consult ICH E10 for more-detailed discussions. 
38 For example, FDA may request updates on a breakthrough therapy designation program in order to provide the 
sponsor with guidance on drug development.   
39 See the guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants.   
Also see the CDER 21st Century Review Process Desk Reference Guide accessible at 
http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ManualofPoliciesProcedures/UCM218757.htm.   
  25 
 
  Contains Nonbinding Recommendations 
 
communication with FDA to ensure that the manufacturing development programs and timing of 
submissions meet the Agencys expectations for licensure or marketing approval.40   
 
When sponsors receive an expedited drug development designation, they should be prepared to 
propose a commercial manufacturing program that will ensure availability of quality product at 
the time of approval.  The proposal should consider estimated market demand and the 
commercial manufacturing development plan.  The proposal should also consider manufacturing 
facilities and a lifecycle approach to process validation.  Additionally, the proposal should 
include a timeline for development of the manufacturing capabilities with goals aligned with the 
clinical development program.  After the initial discussion following designation, frequent 
communication during development will generally facilitate meeting manufacturing development 
goals and product quality goals.   
 
Sponsors of such products should allow for an earlier submission of the CMC section (including 
product quality information) for timely review, and, critically, for inspection activities.41  
Coordination with the sponsor and contract manufacturers may be necessary to ensure that 
manufacturing facilities and equipment are ready for inspection during review of the clinical 
section of the application.  A comprehensive meeting with FDAs product quality review groups 
in advance of submission may facilitate the quality assessment of products designated for 
expedited programs.    
 
Although sponsors must ensure the availability of quality product at the time of approval, FDA 
may exercise some flexibility on the type and extent of manufacturing information that is 
expected at the time of submission and approval for certain components (e.g., stability updates, 
validation strategies, inspection planning, manufacturing scale-up).  The level of flexibility will 
be determined on a case-by-case basis after consideration of factors such as the following: (1) 
product characteristics, (2) seriousness of the condition and medical need, (3) manufacturing 
processes, (4) the robustness of the sponsors quality system, and (5) the strength of the 
sponsors risk-based quality assessment.  FDAs consideration of the sponsors proposal for an 
integrated postmarketing plan will also take into account whether elements of the plan may be 
appropriately executed as a postmarketing commitment or requirement.  For example, FDA will 
consider impacts on clinical performance, such as safety and immunogenicity.  Sponsors should 
meet with the Agency to discuss their proposed plan as soon as possible and no later than the 
pre-NDA or pre-BLA meeting.   
 
B.  Nonclinical Considerations 
 
To ensure timely submission and review of nonclinical data, sponsors should initiate early 
communication with FDA for their nonclinical study programs.  Considerations such as study 
 
40 See the guidance for industry IND Meetings for Human Drugs and Biologics Chemistry, Manufacturing, and 
Controls Information. 
41 For products designated as fast track or breakthrough therapy, this can be accomplished through rolling review 
(see 2.  Submission of Portions of an Application (Rolling Review), 3. Submission of Portions of an Application 
(Rolling Review), and Appendix 2: Processes for Rolling review).  For products submitted under an NDA without 
such a designation, flexibility is permitted in  314.50(d)(1)(iv).  For BLAs without such a designation, there is 
flexibility also to allow an early submission of the CMC section when resources permit. 
 
  26 
 
  Contains Nonbinding Recommendations 
 
protocol modifications, sequence and scheduling of studies, and the need for specific studies 
(e.g., long-term toxicity) may be important in the context of expedited drug development.  FDA 
will provide guidance to sponsors on the development of appropriate and timely nonclinical data 
needed to support an application for marketing approval or licensure.   
 
C.  Clinical Inspection Considerations 
 
Sponsors should anticipate the Agencys need to inspect clinical trials, including, if applicable, 
the analytical component of bioavailability or bioequivalence studies.  Sponsors should be 
prepared for inspections to be scheduled by the Agency early in the application review process 
so inspection results are available to inform the review division and to allow time for the sponsor 
to address significant inspection findings.  To select sites for clinical inspections, it is important 
for reviewers to have timely access to adequate and accurate data in BLA, NDA, or supplement 
submissions.  Sponsors should initiate early communication with FDA about information 
required for inspection planning and conduct.   
 
D.  Companion Diagnostics 
 
Development programs utilizing one or more of the expedited programs described in this 
guidance may involve an in vitro companion diagnostic device.  Sponsors using one of the 
expedited programs for a product that involves an in vitro companion diagnostic device should 
consult FDAs guidance on the topic.42 
 
X.  PAPERWORK REDUCTION ACT OF 1995 
 
This guidance contains information collection provisions that are subject to review by the Office 
of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 
3501-3520).  The time required to complete this information collection is estimated to average 
30 hours per response to prepare a priority review designation request and 70 hours per response 
to prepare a breakthrough therapy designation request, including the time to review instructions, 
search existing data sources, gather the data needed, and complete and review the information 
collection.  Send comments regarding this burden estimate or suggestions for reducing this 
burden to: 
 
Food and Drug Administration 
Center for Drug Evaluation and Research 
Office of Medical Policy 
10903 New Hampshire Avenue, Bldg. 51, rm. 6360 
Silver Spring, MD 20993-0002 
 
This guidance also refers to previously approved collections of information found in FDA 
regulations.  The collections of information in 21 CFR 202.1, certain parts of part 314, part 
601, and sections 506(b)(1), 735, and 736 of the FD&C Act have been approved under OMB 
control numbers 0910-0686, 0910-0001, 0910-0338, and 0910-0297.  An agency may not 
conduct or sponsor, and a pe rson is not required to respond to, a collection of information 
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  https://www.reginfo.gov (search ICR and ente2r 7O  MB control number). 
 
  Contains Nonbinding Recommendations 
 
APPENDIX 1: PROCESSES FOR FAST TRACK, BREAKTHROUGH THERAPY, AND 
PRIORITY REVIEW DESIGNATIONS 
 
This appendix describes general processes applicable to the submission and review of fast track, 
breakthrough therapy, and priority review designations. 
 
A.  Process for Fast Track Designation 
 
1.  When to Send a Designation Submission 
 
Sponsors may request fast track designation when the IND is first submitted or at any time 
thereafter before receiving marketing approval of their BLA or NDA.  The IND and potential 
fast track designation may be discussed before an IND submission in a pre-IND meeting, but a 
decision on designation would await submission of the IND.  As a practical matter, FDA should 
ordinarily receive a fast track designation request no later than the sponsor's pre-BLA or pre-
NDA meeting with the Agency because many of the features of fast track designation will not 
apply after that time.  If a sponsors drug development program is granted fast track designation 
for one indication and has subsequently obtained data to support fast track designation for 
another indication, the sponsor should submit a separate request. 
 
2.  Where to Send a Designation Submission 
 
The IND or amendment should be sent to the IND administrative file to the attention of the 
appropriate review division or office in CDER or CBER.   
 
3.  Content of a Designation Submission  
 
Fast track designation requests should contain the following information (in most cases, this 
information could be captured in approximately 10 to 20 pages):  
 
  If the fast track designation request is submitted to the sponsors IND as an amendment, 
identification of the submission in the cover letter as a REQUEST FOR FAST TRACK 
DESIGNATION in bold, uppercase letters.  If the request is submitted with an initial 
IND, identification of the submission in the cover letter as both an INITIAL 
INVESTIGATIONAL NEW DRUG SUBMISSION and REQUEST FOR FAST 
TRACK DESIGNATION in bold, uppercase letters. 
 
  In the cover letter of the submission, the name of the sponsors contact person and the 
contact persons address, email address, telephone number, and fax number. 
 
  If applicable, the IND application number. 
 
  If available, for drug products, the proprietary name and active ingredient and for 
biological products, the proper name and proprietary name. 
 
  The division or office to which the IND is being submitted or in which it is active. 
  28 
 
  Contains Nonbinding Recommendations 
 
  The proposed indication(s). 
 
  A concise summary of information that supports the fast track designation request for the 
indication being studied, including the following: 
 
  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 
o
medical need and an explanation of how this potential is being evaluated in the 
planned drug development program (e.g., a description of the trials intended to 
evaluate this potential) 
 
  If applicable, a list of documents previously submitted to the IND that is considered 
relevant to the designation request, with reference to submission dates.  Paper 
submissions can be resubmitted to FDA as appendices to the designation request.  
 
4.  FDA Response 
 
FDA will respond to fast track designation requests within 60 calendar days of receipt of the 
request. 
 
a.  Designation letter  
 
If the Agency determines that the criteria for designation as a fast track drug development 
program have been met, the designation letter will: 
 
  State that fast track designation is granted for development of the product for use in 
treating the specific serious condition 
 
  Point out that the sponsor should design and perform studies that can show whether the 
product meets an unmet medical need 
 
  Alert the sponsor to the need for the drug development program to continue to meet the 
criteria for fast track designation 
 
b.  Nondesignation letter 
 
If the Agency determines that a fast track designation request was incomplete or that the drug 
development program failed to meet the criteria for fast track designation, the Agency will send a 
nondesignation letter to the sponsor.  The nondesignation letter will state that fast track 
designation is not granted and explain the reasons for the Agency's decision.   
 
5.  Continued Designation as a Fast Track Development Program 
 
Over the course of drug development, it can be expected that some products granted fast track 
designation will not continue to meet the criteria for fast track designation.  A drug product in a 
  29 
 
  Contains Nonbinding Recommendations 
 
fast track development program may not continue to meet the criteria if the drug: (1) no longer 
demonstrates a potential to address unmet medical need or (2) is not being studied in a manner 
that shows the drug product can treat a serious condition and meets an unmet medical need.  The 
drug product may no longer demonstrate a potential to address unmet medical need, for example, 
if a new product was approved under a traditional approval that addressed the same need or if 
emerging clinical data failed to show that the product in a fast track development program had 
the anticipated advantage over available therapy.  For products in fast track drug development 
programs, the Agency expects that the appropriateness of considering particular drug 
development plans as part of the fast track program will be discussed and evaluated during the 
drug development process, including at the end-of-phase 2 meeting and the pre-BLA or pre-
NDA 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 when the IND is first 
submitted or at any time thereafter, they should not send breakthrough therapy designation 
requests until they have preliminary clinical evidence indicating that . . . the drug may 
demonstrate substantial improvement over existing therapies on 1 or more clinically significant 
endpoints.43  FDA therefore expects that in most cases breakthrough therapy designation 
requests would be submitted as an amendment to the IND.  Ideally, FDA should receive a 
breakthrough therapy designation request before initiation of the clinical trial(s) intended to serve 
as the primary basis for demonstration of efficacy if most of the benefits of designation are to be 
obtained.  Because the primary intent of breakthrough therapy designation is to develop evidence 
needed to support approval as efficiently as possible, FDA anticipates that breakthrough therapy 
designation requests will rarely be made after the submission of an original BLA or NDA or a 
supplement.  If a sponsors drug development program is granted breakthrough therapy 
designation for one indication and has subsequently obtained preliminary clinical evidence to 
support breakthrough therapy designation for another indication, the sponsor should submit a 
separate request. 
 
If a sponsor has not requested breakthrough therapy designation, FDA may suggest that the 
sponsor consider submitting a request if: (1) after reviewing available data and information, the 
Agency thinks the drug development program may meet the criteria for breakthrough therapy 
designation and (2) the remaining drug development program and review can benefit from the 
designation.  However, the Agency still needs to review the submitted request (including 
preliminary clinical evidence) to determine if it meets the criteria for breakthrough therapy 
designation.  A suggestion by the Agency that a sponsor consider submitting a request for 
 
43 Section 506(a)(1) of the FD&C Act. 
  30 
 
  Contains Nonbinding Recommendations 
 
breakthrough therapy designation is advisory and should not be interpreted as guaranteeing 
breakthrough therapy designation once a request is submitted and reviewed. 
 
2.  Where to Send a Designation Submission 
 
The IND or amendment should be submitted to the IND administrative file to the attention of the 
appropriate review division or office in CDER or CBER. 
 
3.  Content of a Designation Submission 
 
Breakthrough therapy designation requests should contain the following information (in most 
cases, this information could be captured in approximately 10 to 20 pages): 
 
  If the breakthrough therapy designation request is submitted to the sponsors IND as an 
amendment, identification of the submission in the cover letter as a REQUEST FOR 
BREAKTHROUGH THERAPY DESIGNATION in bold, uppercase letters.  If the 
request is submitted with an initial IND, identification of the submission in the cover 
letter as both an INITIAL INVESTIGATIONAL NEW DRUG SUBMISSION and 
REQUEST FOR BREAKTHROUGH THERAPY DESIGNATION in bold, 
uppercase letters.  
 
  In the cover letter of the submission, the name of the sponsors contact person and the 
contact persons address, email address, telephone number, and fax number. 
 
  If applicable, the IND application number. 
 
  If available, for drug products, the proprietary name and active ingredient and for 
biological products, the proper name and proprietary name. 
 
  The division or office to which the IND is being submitted or in which it is active.  
 
  The proposed indication(s).  
 
  A concise summary of information that supports the breakthrough therapy designation 
request for the indication being studied, including the following: 
 
  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 
o
improvement over available therapies.44  FDA does not expect the sponsor to 
submit primary data (data sets); but, the sponsor should describe the preliminary 
clinical evidence, including, for example, a brief description of available therapies 
(if there are any) and their effectiveness; justification for the comparator selected 
 
44 If the designation is being submitted with the IND, examples of information that could be submitted to support a 
designation request include data from foreign clinical trials not conducted under IND, a different formulation or 
route of administration, a use in an unrelated indication, or the published literature.   
  31 
 
  Contains Nonbinding Recommendations 
 
for the clinical studies, the study design, the population studied, and the endpoint 
used; and a brief description of the study results and statistical analyses 
(including, for example, subgroup analysis). 
 
  If applicable, a list of documents previously submitted to the IND that is considered 
relevant to the designation request, with reference to submission dates.  Paper 
submissions can be resubmitted to FDA as appendices to the designation request. 
 
4.  FDA Response 
 
FDA will respond to 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:  
 
  State that breakthrough therapy designation is granted for development of the product for 
use in treating the specific serious condition 
 
  Explain that FDA will work closely with the sponsor to provide guidance on subsequent 
development, including providing advice on generating evidence needed to support the 
drug approval in an efficient manner 
 
  Alert the sponsor to the need for the drug development program to continue to meet the 
criteria for breakthrough therapy designation 
 
b.  Nondesignation letter  
 
If the Agency determines that a breakthrough therapy designation request was incomplete or that 
the drug development program failed to meet the criteria for breakthrough therapy designation, 
the Agency will send a nondesignation letter to the sponsor.  The nondesignation letter will state 
that a breakthrough therapy designation is not granted and explain the reasons for the Agencys 
decision.  Where appropriate, the letter may also include advice to the sponsor regarding 
subsequent development, including what would be needed in a new breakthrough therapy 
designation request. 
 
5.  Continued Designation as a Breakthrough Therapy Development Program 
 
Over the course of drug development, it can be expected that some products granted 
breakthrough therapy designation will no longer be considered a breakthrough therapy.  For 
example, a drug development program may be granted breakthrough therapy designation using 
early clinical testing that shows a much higher response rate than available therapies.  However, 
subsequent interim data derived from a larger study may show a response that is substantially 
smaller than the response seen in early clinical testing.  Another example is where breakthrough 
  32 
 
  Contains Nonbinding Recommendations 
 
therapy designation is granted to two drugs that are being developed for the same use.  If one of 
the two drugs gains traditional approval, the other would not retain its designation unless its 
sponsor provided evidence that the drug may demonstrate substantial improvement over the 
recently approved drug.  Additionally, if the sponsor recognizes that the development program 
designated as breakthrough therapy will no longer be pursued, the sponsor should inform the 
Agency of this change. 
 
When breakthrough therapy designation is no longer supported by emerging data or the 
designated drug development program is no longer being pursued, the Agency may choose to 
send a letter notifying the sponsor that the program is no longer designated as a breakthrough 
therapy development program.  Consistent with FDAs commitment to communicate frequently, 
and in an interactive manner, with sponsors of drugs designated as breakthrough therapies, FDA 
will notify the sponsor of its intent to rescind and will offer the sponsor an opportunity to justify 
its products continued designation.  FDA recognizes that sponsors of products that have had 
their breakthrough therapy designation rescinded because available data no longer support the 
designation may still have sufficient evidence after completion of the drug development program 
to support marketing approval. 
 
C.  Process for Priority Review Designation 
 
FDA determines whether an application qualifies for priority review (versus standard review) for 
every application, not just when priority review is requested by the applicant.  However, an 
applicant may expressly request priority review as described in the following sections. 
 
1.  When to Send a Designation Submission 
 
Sponsors may request priority review designation when they submit an original BLA, NDA, or 
efficacy supplement.  The Agency does not anticipate that priority review designation requests 
will be made after the filing of a BLA, NDA, or efficacy supplement.     
 
2.  Where to Send a Designation Submission 
 
Priority review designation requests may be submitted with the original BLA, NDA, or efficacy 
supplement to the attention of the appropriate review division or office in CDER or CBER.   
 
3.  Content of a Designation Submission 
 
Priority review designation requests should contain the following information: 
 
  Identification of the submission in the cover letter as a REQUEST FOR PRIORITY 
REVIEW DESIGNATION in bold, uppercase letters. 
 
  In the cover letter of the submission, the name of the sponsors contact person and the 
contact persons address, email address, telephone number, and fax number.   
 
  33 
 
  Contains Nonbinding Recommendations 
 
  If available, for drug products, the proprietary name and active ingredient and for 
biological products, the proper name and proprietary name. 
 
  The proposed indication(s). 
 
  A concise summary of information that supports the priority review designation request, 
including the following: 
 
  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 
o
safety or effectiveness of the treatment, prevention, or diagnosis of a serious 
condition    
 
4.  FDA Response 
 
FDA will inform the applicant in writing of a priority review designation by day 60 of the 
review.  The division will inform the applicant in writing of a standard review designation by 
day 74 of the review.  Applications that are not filed do not receive a review designation. 
 
5.  Continued Priority Review Designation 
 
After priority review designation is assigned, the timeline will not change during the first review 
cycle, even if a redetermination of review status is made because of approval of other drugs, 
availability of new data, or submission of a request for formal dispute resolution by the 
applicant.  In addition, applications filed over protest are assigned a standard review.  If the 
application is resubmitted after FDAs refuse-to-file decision or if the application is withdrawn 
before FDAs action and resubmitted, FDA will make its determination of review designation 
based on the resubmitted application.
  34 
 
  Contains Nonbinding Recommendations 
 
APPENDIX 2: PROCESSES FOR ROLLING REVIEW 
 
This appendix describes general processes applicable to the submission and review of portions of 
an application, a feature of fast track designation (see section V.B.2.) and breakthrough therapy 
designation (see section V1.B.3.). 
 
A.  Agreement on Proposal 
 
Sponsors obtain preliminary Agency agreement on the proposal at the pre-BLA or pre-NDA 
meeting or earlier for products with breakthrough therapy designation (e.g., end-of-phase 2 
meeting).  At the meeting, the sponsor and the review division should discuss: (1) the data 
that will be used to support effectiveness, (2) the schedule for submission of each portion of 
the BLA or NDA, and (3) a description of portions of the application to be submitted 
separately.   
 
A request to submit portions of an application ordinarily should be included in the 
information package for the pre-BLA or pre-NDA meeting.  If a sponsor seeks to submit 
portions of an application to the IND after the pre-BLA or pre-NDA meeting, the sponsor 
should make such a request and provide a proposed schedule for submission of portions of an 
application to the IND as soon as possible. 
 
A request for submission of portions of an application should be sent as an amendment to the 
IND; attach Form FDA 1571.  The amendment should be clearly identified as a REQUEST 
FOR SUBMISSION OF PORTIONS OF AN APPLICATION in bold, uppercase letters.  
FDA responds to sponsors requests for submission of portions of an application by letter.  
FDA also responds to changes to an agreement to accept portions of an application by letter. 
 
B.  Portions of an Application Eligible for Early Submission 
 
Generally, the Agency accepts for submission a complete section of a BLA or NDA only, 
such as the entire CMC section, toxicology section, or clinical section.45  A section of a BLA 
or NDA should be submitted for review in a form adequate to have been included in a 
complete BLA or NDA submission.  Drafts should not be included in a submission; if final 
reports need to be updated, the applicant should submit a formal amendment to the BLA or 
NDA with the revised information.  Occasionally, the Agency may, in its discretion, accept 
less than a complete section if the Agency determines that such a subsection would constitute 
a reviewable unit and be useful in making the review process more efficient (e.g., less than a 
complete section could be a CMC section lacking final consistency lot data and long-term 
stability data, a toxicology section lacking chronic toxicology data, final study reports for 
some or all of the principal controlled trials without integrated summaries).  The sponsor 
should confirm these subsections are final reports. 
 
At the pre-BLA or pre-NDA meeting, the Agency and the sponsor should work together to 
clearly define the parameters of accepting an incomplete section and to determine whether 
 
45 Form FDA 356h may be a useful guide to items in a BLA or NDA. 
  35  Contains Nonbinding Recommendations 
 
FDA could conduct a meaningful review of the submission before receiving the missing 
information. 
 
C.  Submission of User Fees 
 
A sponsor is required to pay applicable fees as stated in section 736 of the FD&C Act before 
FDA may commence review of any portion of an application.  The applicant should submit Form 
FDA 3397 with applicable user fees and follow the same procedures as those followed when a 
complete application is submitted. 
 
D.  Commencement of Review 
 
If FDA accepts a portion of an application, this does not necessarily mean that review will 
commence or proceed before the complete application is submitted.  Actual commencement and 
scheduling of review depends on many factors, including staffing, workload, competing 
priorities, timeline for completing the application, and the perceived efficiency of commencing 
review before receipt of the complete submission. 
 
E.  Calculation of Review Time 
 
The review clock will not begin until the applicant informs the Agency that a complete BLA 
or NDA was submitted.46  After the Agency is notified of the complete application, we will 
make a filing determination within the usual time.47 
 
 
46 Section 506(d)(2) of the FD&C Act provides that any time period for review of human drug applications shall not 
apply until the date on which the application is complete.   
47 See  314.101, CDER MAPP 6025.4, Good Review Practice: Refuse to File, available on the Internet at 
http://www.fda.gov/downloads/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/manualofpoliciespr
ocedures/ucm370948.htm and CBER SOPP 8404, Refusal to File Procedures for Biologic License Applications 
(August 27, 2007), available on the Internet at 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ProceduresSOPPs/ucm07
3474.htm. 
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