Labeling for Human Prescription 
Drug and Biological Products 
Approved Under the Accelerated 
Approval Regulatory Pathway
 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
January 2019 
Labeling 
   
Labeling for Human Prescription 
Drug and Biological Products 
Approved Under the Accelerated 
 
Approval Regulatory Pathway
Guidance for Industry 
 
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Center for Drug Evaluation and Research 
Food and Drug Administration 
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https://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) 
 
January 2019 
Labeling
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  ACCELERATED APPROVAL LABELING CONSIDERATIONS ........................... 3 
A.  Indication Approved Under Accelerated Approval .................................................................... 3 
1. Limitations of Usefulness and Clinical Benefit Uncertainty ............................................................ 4 
2. Continued Approval ......................................................................................................................... 4 
B.  When Clinical Benefit Has Been Verified .................................................................................... 5 
C.  Withdrawal of an Accelerated Approved Indication .................................................................. 5 
1. Lack of Evidence Concerning the Withdrawn Indication ................................................................ 6 
2. Safety Information Concerning the Withdrawn Indication .............................................................. 6 
  Contains Nonbinding Recommendations 
Labeling for Human Prescription Drug and Biological Products 
Approved Under the Accelerated Approval Regulatory Pathway 
Guidance for Industry1 
 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
 
 
I.  INTRODUCTION  
 
This guidance is intended to assist applicants in developing the INDICATIONS AND USAGE 
section of labeling for human prescription drug and biological products that are approved under 
the accelerated approval regulatory pathway (hereafter accelerated approval) as defined in 
section 506(c) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and 21 CFR part 314, 
subpart H, or 21 CFR part 601, subpart E.  More specifically, this guidance focuses on 
indications for drugs2 approved via accelerated approval on the basis of a surrogate endpoint or a 
clinical endpoint other than survival or irreversible morbidity.3  This guidance also addresses 
labeling considerations for indications that were approved under accelerated approval and for 
which clinical benefit subsequently has been verified and the FDA terminates the conditions of 
accelerated approval under 21 CFR 314.560 or 21 CFR 601.46.  In addition, this guidance 
addresses labeling considerations when the FDA withdraws approval of an indication that had 
been approved through the accelerated approval pathway while other indications for the drug 
remain approved. 
 
In general, FDAs guidance documents 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.  
 
                                                 
1 This guidance has been prepared by the Office of New Drugs in the Center for Drug Evaluation and Research in 
cooperation with the Center for Biologics Evaluation and Research at the Food and Drug Administration.  
 
2 The term drug as used in this guidance refers to human drugs and biological products. 
 
3 This guidance focuses on indications that are granted accelerated approval status based on 21 CFR 314.510 and 
21 CFR 601.41.  This guidance does not address 21 CFR 314.520 and 21 CFR 601.42. 
  1  Contains Nonbinding Recommendations 
 
II.  BACKGROUND 
 
The accelerated approval process is one of several approaches used by the FDA to expedite the 
development of drugs for serious or life-threatening diseases and conditions.  Section 506(c) of 
the FD&C Act provides that the 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 purposes of this guidance, these categories of endpoints are referred 
to as surrogate endpoints and intermediate clinical endpoints.   
 
This guidance focuses on how accelerated approval based on a surrogate endpoint, or on an 
intermediate clinical endpoint, is represented in the INDICATIONS AND USAGE section of 
labeling.  In each case, the effect on the endpoint is established by the results of adequate and 
well-controlled clinical trials.4  However, the accelerated approval is subject to the requirement 
that the applicant conduct additional postmarketing clinical trials to verify and describe the 
drugs clinical benefit,5 where there is uncertainty as to the relationship of the surrogate endpoint 
to the clinical benefit, or of the intermediate clinical endpoint to ultimate outcome.  Clinical 
benefit is verified when postmarketing clinical trials show that the drug provides a clinically 
meaningful positive therapeutic effect, usually an effect on how a patient feels (e.g., symptom 
relief), functions (e.g., improved mobility), or survives.6  
 
Labeling for human prescription drugs must contain a summary of the essential scientific 
information needed for the safe and effective use of the drug.7  Applications submitted for 
accelerated approval must include labeling that conforms to the content and format requirements 
for human prescription drug labeling delineated in 21 CFR 201.56(d) and 201.57.  Labeling for 
drugs approved under the accelerated approval framework is in most ways the same as labeling 
for drugs with traditional approval.   
 
However, if a drug is granted accelerated approval based on a surrogate endpoint, the 
INDICATIONS AND USAGE section of the labeling must also include a succinct description 
of the limitations of usefulness of the drug and any uncertainty about anticipated clinical 
                                                 
4 See 21 CFR 314.126. 
 
5 See section 506(c)(2)(A) of the FD&C Act;  314.510 and 601.41.  
 
6 See the guidance for industry Expedited Programs for Serious Conditions  Drugs and Biologics (May 2014).  
We update guidances periodically.  For the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.  
 
7 See 21 CFR 201.56(a)(1). 
  2  Contains Nonbinding Recommendations 
benefits, with reference to the Clinical Studies section for a discussion of the available 
evidence, as noted in  201.57(c)(2)(i)(B).8  
 
 
III.  ACCELERATED APPROVAL LABELING CONSIDERATIONS 
 
Certain special labeling considerations arise when the FDA approves a drug (or an indication) 
under the accelerated approval pathway, including the following:  (1) information to be included 
in the INDICATIONS AND USAGE section of labeling; (2) revisions needed when 
postmarketing clinical trials have verified and adequately described the drugs clinical benefit for 
an indication granted under accelerated approval; and (3) revisions needed when the FDA 
withdraws approval of one or more indications granted under accelerated approval for a drug 
whose labeling includes other approved indications.   
 
A.  Indication Approved Under Accelerated Approval   
 
Under FDA regulations, the information included in the INDICATIONS AND USAGE section 
of labeling for drugs approved under accelerated approval must include the indication (i.e., the 
disease or condition that the drug treats, prevents, mitigates, cures, or diagnoses),9 as well as a 
succinct description of the limitations of usefulness of the drug and any uncertainty about 
anticipated clinical benefits. . . .10  The information in this section generally should also 
acknowledge that the drug was approved based upon accelerated approval and that continued 
approval for the drug (or indication) may be contingent upon verification and description of 
clinical benefit in a confirmatory trial or trials. 
 
The following is an example of how these elements should be represented in the INDICATIONS 
AND USAGE section of the full prescribing information: 
 
DRUG X is indicated for {state indication}.  This indication is approved under accelerated 
approval based on {state effect on surrogate endpoint or intermediate clinical endpoint that 
supported the accelerated approval} [see Clinical Studies (14.X)].  Continued approval for 
this indication may be contingent upon verification and description of clinical benefit in a 
confirmatory trial(s). 
 
A similar presentation should be used under the Indications and Usage heading in Highlights, 
except that the cross-reference to the CLINICAL STUDIES section is not necessary for 
Highlights. 
                                                 
8 The FDA interprets this provision as applying not only to drugs approved under accelerated approval on the basis 
of a surrogate endpoint, but also drugs approved under accelerated approval based on an effect on a clinical endpoint 
other than survival or irreversible morbidity.  Under  201.57(c)(2)(i)(B), the requirement to provide a succinct 
description of limitations of usefulness and any uncertainty about anticipated clinical benefits of a drug also applies 
to situations where evidence is available to support the safety and effectiveness of a drug only in selected 
subgroups of the larger population (e.g., patients with mild disease or patients in a special age group). . . .    
 
9 See  201.57(c)(2). 
 
10 See  201.57(c)(2)(i)(B). 
  3  Contains Nonbinding Recommendations 
 
A more detailed description of two elements of the INDICATIONS AND USAGE section is 
provided below with examples.   
 
1.  Limitations of Usefulness and Clinical Benefit Uncertainty 
 
The INDICATIONS AND USAGE section for drugs (or indications) approved based on a 
surrogate or intermediate clinical endpoint should state the endpoint used in the clinical trials that 
provided substantial evidence to support accelerated approval, and the limitations of that 
endpoint.  In addition, a cross-reference to the CLINICAL STUDIES section for a discussion of 
the available evidence should be included.  The description of the basis for approval should 
immediately follow the indication rather than appear under a separate heading or paragraph.  
 
The following is an example of a statement that states the endpoint used in the clinical trials to 
support the accelerated approval: 
 
This indication is approved under accelerated approval based on tumor response rate [see 
Clinical Studies (14.1)].   
 
Including the term accelerated approval is informative because it provides the framework and 
rationale for the other indication elements that are unique to drugs approved in this manner.   
 
Simply reporting the endpoint used may convey sufficient information about uncertainty with 
regard to the limitations of usefulness of the drug and of uncertainty about anticipated clinical 
benefits (the benefit that is anticipated based upon the surrogate or intermediate clinical endpoint 
used to support accelerated approval).  In other circumstances, additional context about the 
approval should be included in the indication by identifying the clinical outcome(s) that are 
expected (based on the effect demonstrated on the surrogate or intermediate clinical endpoint) 
but not yet established.    
 
The following is an example of a statement that provides additional context about the approval 
by identifying the clinical outcome(s) that have not been established.  Such information should 
be described immediately after the sentence that identifies the endpoint that supported 
accelerated approval. 
 
This indication is approved under accelerated approval based on a reduction in alkaline 
phosphatase [see Clinical Studies (14.1)].  An improvement in survival or disease-related 
symptoms have not been established.  
 
2.  Continued Approval 
 
For indications approved under accelerated approval based on a surrogate or intermediate clinical 
endpoint, the applicant generally is required to conduct additional postmarketing clinical trials to 
verify and describe the drugs clinical benefit.  Although regulatory postmarketing study 
requirements typically are not included in labeling, a brief summary of the confirmatory study 
requirements can further emphasize the limitations of the clinical study results supporting the 
  4  Contains Nonbinding Recommendations 
accelerated approval.  Therefore, the INDICATIONS AND USAGE section should include a 
statement explaining that continued approval for the indication may be subject to the requirement 
that confirmatory trials verify the drugs clinical benefit.  When summarizing the postmarketing 
study requirements, the statement should refer to verification and description of clinical benefit 
as described in the following example.   
 
Continued approval for this indication may be contingent upon verification and description of 
clinical benefit in a confirmatory trial(s). 
 
B.  When Clinical Benefit Has Been Verified  
 
Following successful verification and description of clinical benefit in the postmarketing studies, 
the information in the INDICATIONS AND USAGE section should be revised.  The indication 
generally should reflect the population and condition for which there is substantial evidence of 
effectiveness, including any new or remaining limitations of use.  The statements concerning 
limitations of usefulness and continued approval should be removed or revised, as appropriate.  
In addition, other sections of labeling (e.g., ADVERSE REACTIONS and CLINICAL 
STUDIES) should be revised, as appropriate, to reflect the new data (e.g., the CLINICAL 
STUDIES section generally should be revised to include a description of the clinical studies that 
verified clinical benefit). 
 
C.  Withdrawal of an Accelerated Approved Indication  
 
Approval of a drug or indication approved under accelerated approval may be withdrawn either 
at the request of the applicant or by the FDA for the following reasons (among others): 
 
  The applicant fails to conduct any required postmarketing study with due diligence 
 
  A study required to verify and describe the predicted effect on irreversible morbidity or 
mortality or other clinical benefit of the drug fails to verify and describe such effect or 
benefit  
 
  Other evidence demonstrates that the drug is not safe or effective under the conditions of 
use11  
 
If the accelerated approval indication is withdrawn, but the drug remains approved for other 
indications, the labeling must be revised.12  For example, it may be necessary to remove 
information concerning the withdrawn indication from several sections (e.g., INDICATIONS 
AND USAGE, DOSAGE AND ADMINISTRATION, and CLINICAL STUDIES) so that the 
labeling does not imply or suggest that the drug is approved for the withdrawn indication.13  In 
                                                 
11 See section 506(c)(3) of the FD&C Act (21 U.S.C. 356(c)(3)); 21 CFR 314.530 and 601.43.  
 
12 See  201.56(a)(2). 
 
13 See  201.57(c)(2)(iv) and (v). 
  5  Contains Nonbinding Recommendations 
addition to removing information, it may sometimes be appropriate to add to the labeling new 
information concerning the withdrawn indication, as noted below. 
 
1.  Lack of Evidence Concerning the Withdrawn Indication 
 
Under  201.57(c)(2)(ii), if there is a common belief that the drug may be effective for a certain 
use, or if there is a common use of the drug for a condition, but the preponderance of evidence 
related to the use or condition shows that the drug is ineffective or that the therapeutic benefits of 
the drug do not generally outweigh its risks, the FDA may require that the INDICATIONS AND 
USAGE section state that there is lack of evidence that the drug is effective or safe for that use.  
When accelerated approval of an indication is withdrawn, the FDA may require that the labeling 
be revised to include a limitation of use concerning the withdrawn indication.14  
 
2.  Safety Information Concerning the Withdrawn Indication 
 
Under  201.57(c)(6)(i), a specific warning relating to a use not provided for under the 
INDICATIONS AND USAGE section may be required by the FDA in the WARNINGS AND 
PRECAUTIONS section of labeling if a drug is commonly prescribed for a disease or condition 
and such usage is associated with a clinically significant risk or hazard.  Because the drug was 
previously indicated for the now-withdrawn use and may continue to be considered for that use 
by some health care providers, clinically significant adverse reactions or risks associated with the 
withdrawn indication may be appropriate to include in the WARNINGS AND PRECAUTIONS 
and/or ADVERSE REACTIONS sections of the revised labeling.  The description of the risk or 
hazard also should be accompanied by a statement that the drug is not approved for the 
withdrawn indication.  
 
                                                 
14 See the draft guidance for industry Indications and Usage Section of Labeling for Human Prescription Drug and 
Biological ProductsContent and Format (July 2018).  When final, this guidance will represent the FDAs current 
thinking on this topic.  For the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.  
  6