Failure to Respond to an 
ANDA Complete Response 
Letter Within the Regulatory 
Timeframe 
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) 
 
 
December 2022 
Generic Drugs 
 
Revision 1
         
Failure to Respond to an 
ANDA Complete Response 
Letter Within the Regulatory 
Timeframe 
Guidance for Industry 
 
 
Additional copies are available from: 
Office of Communications, Division of Drug Information  
Center for Drug Evaluation and Research 
Food and Drug Administration 
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Silver Spring, MD 20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov  
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm  
or 
Office of Communication, Outreach, and Development  
Center for Biologics Evaluation and Research 
Food and Drug Administration 
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Silver Spring, MD  20993-0002 
Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-
guidances 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
December 2022 
Generic Drugs 
 
Revision 1 
      Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  DISCUSSION .................................................................................................................... 3 
A.  Failure to Respond to a CRL Within 1 Year ............................................................................... 3 
B.  Failure to Respond to a CRL Within the Extended Time Period Granted by FDA ................ 4 
C.  Submission of a Request for an Extension to Respond to a CRL .............................................. 4 
D.  Evaluation of a Request for an Extension to Respond to a CRL ............................................... 5 
E.  Withdrawal of an ANDA ............................................................................................................... 6 
i  Contains Nonbinding Recommendations 
 
Failure to Respond to an ANDA Complete Response Letter Within 
the Regulatory Timeframe  
Guidance for Industry 1 
 
 
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 of abbreviated new drug applications (ANDAs), 
which were submitted under section 505(j) of the Federal Food, Drug, and Cosmetic Act (FD&C 
Act) (21 U.S.C. 355(j)), in responding to complete response letters (CRLs) from FDA.  As 
described in regulation, ANDA applicants are required to take action after receiving a CRL.2  
The guidance revises the guidance of the same title issued in July 2022.  This revision is being 
issued to incorporate the performance goals outlined in the Generic Drug User Fee Amendments 
Reauthorization Performance Goals and Program Enhancements Fiscal Years 2023-2027 
(GDUFA III commitment letter).3  This guidance provides information and recommendations 
regarding potential courses of action for an ANDA applicant after issuance of a CRL, as well as 
the actions that FDA may take if the applicant fails to respond to that CRL.4    
 
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 guidance means that something is suggested or recommended, but 
not required.  
 
1 This guidance has been prepared by the Division of Policy Development in the Office of Generic Drug Policy in 
the Center for Drug Evaluation and Research, in cooperation with the Center for Biologics Evaluation and Research, 
at the Food and Drug Administration.  You may submit comments on this guidance at any time. Submit comments 
to Docket No. FDA-2020-D-1548 (available at https://www.regulations.gov/docket/FDA-2020-D-1548). 
2 21 C.F.R. 314.110(b). 
3 The GDUFA III commitment letter is available at https://www.fda.gov/media/153631/download. 
4 See 21 CFR 314.110(b)-(c).  This guidance applies to applications which the agency has acted upon by issuing a 
CRL. A CRL may contain major and/or minor deficiencies.  See FDAs guidance for industry ANDA Submissions  
Amendments to Abbreviated New Drug Applications Under GDUFA (July 2018).  We update guidances 
periodically.  For the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
 
  1  Contains Nonbinding Recommendations 
 
 
 
II.  BACKGROUND 
 
The Generic Drug User Fee Amendments of 2012 (GDUFA I)5 amended the FD&C Act to 
authorize FDA to assess and collect user fees to provide the Agency with resources6 to help 
ensure patients have access to quality, affordable, safe, and effective generic drugs.  Generic 
Drug User Fee Amendments (GDUFA) fee resources bring greater predictability and timeliness 
to the review of generic drug applications.  GDUFA has been reauthorized every 5 years to 
continue FDAs ability to assess and collect GDUFA fees, and this user fee program has been 
reauthorized two times since GDUFA I, most recently in Continuing Appropriations and Ukraine 
Supplemental Appropriations Act, 20237 (GDUFA III).  As described in the GDUFA III 
commitment letter applicable to this latest reauthorization, FDA has agreed to performance goals 
and program enhancements regarding aspects of the generic drug assessment program that build 
on previous authorizations of GDUFA.  New enhancements to the program are designed to 
maximize the efficiency and utility of each assessment cycle, with the intent of reducing the 
number of assessment cycles for ANDAs and facilitating timely access to generic medicines for 
American patients.  
 
Once an ANDA has been received for review, FDA performs a substantive assessment to 
determine if the ANDA meets the regulatory requirements for approval.  FDA communicates any 
deficiencies identified during this assessment in a CRL to the ANDA applicant.8  After receiving 
a CRL, as described in 21 CFR 314.110 an applicant must (1) resubmit its ANDA (i.e., submit 
all materials needed to fully address all deficiencies identified in the CRL),9 (2) withdraw its 
ANDA, or (3) request the opportunity for a hearing.10  If an applicant fails to take one of these 
three actions within 1 year after issuance of a CRL, FDA may consider this failure to be a 
request to withdraw the ANDA unless the applicant has requested an extension of time to 
address all deficiencies identified in the CRL.11  In addition, as described in the GDUFA III 
commitment letter, FDA agreed to reclassify a minor amendment as a major amendment if the 
amendment is submitted more than 1 year after the date FDA issued the CRL, unless the ANDA 
falls under one of three exceptions that are further described in section III.A of this guidance.12 
 
5 Title III of the Food and Drug Administration Safety and Innovation Act, Public Law 112-144. 
6 User fees are available for obligation in accordance with appropriations acts.  
7 See Division F, Title III, of the Continuing Appropriations and Ukraine Supplemental Appropriations Act, 2023 
(Public Law 117-180). 
8 21 CFR 314.110.  A CRL is a written communication to an applicant from FDA usually describing all of the 
deficiencies that the Agency has identified in an NDA or ANDA that must be satisfactorily addressed before it can 
be approved.  21 CFR 314.3(b). See also 21 CFR 314.102. 
9 See 21 CFR 314.3(b) (defining resubmission).  Applicants may address the deficiencies identified in a CRL by 
submitting an amendment to their application.  See FDAs guidance for industry ANDA Submissions  Amendments 
to Abbreviated New Drug Applications Under GDUFA (July 2018).   
10 21 CFR 314.110(b). 
11 21 CFR 314.110(c)(1).   
12 GDUFA III commitment letter at 17. 
  2  Contains Nonbinding Recommendations 
 
 
Under the GDUFA program, FDA has seen a steady increase of ANDAs pending with industry 
for more than a year.  Historically, FDA, in its discretion, has liberally granted requests for 
multiple extensions to respond to an individual CRL to the detriment of the ANDA assessment 
process.  Lengthy response times because of multiple extensions, which can result in applicants 
submitting an amendment addressing deficiencies years after the initial assessment of the ANDA 
and issuance of the CRL, are disruptive to the assessment process and can create additional 
assessment cycles.  Over time, information submitted in the original ANDA can become obsolete 
because of changes such as new or revised United States Pharmacopeia requirements, labeling 
changes to the reference listed drug (RLD), or other events such as a facility evaluation 
becoming outdated.  In addition, over time, FDA assessment staff may have changed, and it may 
take time for another assessor(s) to familiarize themselves with the original ANDA.  For these 
reasons, assessing an amendment submitted years after the initial ANDA assessment and 
issuance of the CRL diverts the Agencys limited resources from the review of other 
applications. 
 
 
III.  DISCUSSION     
 
As described above, FDAs regulations provide that if an applicant wishes to continue pursuing 
approval of its ANDA, an applicant should submit all materials needed to fully address all 
deficiencies identified in the CRL within 1 year of issuance of the CRL.13  If an applicant wishes 
to continue to seek approval in this manner and determines it will be unable to address the 
deficiencies within 1 year of issuance of the CRL, the applicant should submit an amendment to 
its ANDA requesting an extension of time to address those deficiencies.  The applicant should 
submit its request for an extension on or before the date the response to the CRL is due.   
 
A.  Failure to Respond to a CRL Within 1 Year 
 
If an applicant fails to submit to FDA all materials needed to fully address all deficiencies 
identified in the CRL within 1 year after issuance of the CRL (or take either of the other two 
actions prescribed by regulation and that are described above), FDA may consider this failure to 
be a request by the applicant to withdraw the ANDA.14  FDA will notify the applicant in writing 
and the applicant will have 30 days from the date of that notification to (1) explain why the 
ANDA should not be withdrawn and (2) request an extension of time to address all deficiencies 
identified in the CRL.15  To best facilitate FDAs consideration of the reasonableness of the 
request under 21 CFR 314.110(c), we recommend that the applicant provide the information 
described in section III.C of this guidance, and FDA will evaluate that request for an extension of 
time by considering, among other relevant information, the factors identified in section III.D of 
 
13 FDA regulations also provide that an applicant can request an opportunity for a hearing on the question of whether 
there are grounds for denying approval of the ANDA.  21 CFR 314.110(b). 
14 21 CFR 314.110(b)-(c).   
15 21 CFR 314.110(c)(2). 
  3  Contains Nonbinding Recommendations 
 
this guidance.  If the applicant does not respond to the notification within 30 days, FDA will 
deem the ANDA withdrawn and will notify the applicant of the withdrawal in writing.16    
 
In addition, as described in the GDUFA III commitment letter, FDA will reclassify a minor 
amendment as a major amendment if the amendment is submitted more than 1 year after the date 
FDA issued the CRL, unless the ANDA is for a product on the drug shortage list under section 
506E of the FD&C Act (21 U.S.C. 356e), or is the subject of a response to a Public Health 
Emergency as declared by the Secretary of the U.S. Department of Health and Human Services 
under section 319 of the Public Health Service Act (42 U.S.C. 247d), or is anticipated to be 
subject to the same criteria as apply to such a declaration, at the time of submission.17   
 
B.  Failure to Respond to a CRL Within the Extended Time Period Granted by 
FDA 
 
If FDA grants the applicants request for an extension to respond to a CRL but the applicant fails 
to submit an amendment which addresses all the deficiencies identified in the CRL within the 
extended time period granted by FDA or to request an additional extension, FDA may consider 
this failure to be a request by the applicant to withdraw the ANDA.18  FDA will notify the 
applicant in writing and the applicant will have 30 days from the date of that notification to (1) 
explain why the ANDA should not be withdrawn and (2) request another extension of time to 
address all deficiencies identified in the CRL.19  To best facilitate FDAs consideration of the 
reasonableness of the request under 21 CFR 314.110(c), we recommend that the applicant 
provide the information described in section III.C of this guidance.  If the applicant does not 
respond to the notification within 30 days, FDA will deem the ANDA withdrawn and notify the 
applicant of the withdrawal in writing.20    
       
C.  Submission of a Request for an Extension to Respond to a CRL   
 
Applicants should submit a request for an extension to respond to a CRL via an amendment to 
their ANDA.  We recommend that a request address the following issues: 
 
  A justification or reason as to why the applicant needs additional time to respond to the 
CRL.  The justification should include: 
 
  For an applicant submitting a request for a first extension, the reason why it was 
o
unable to respond to the deficiencies identified in the CRL within 1 year 
 
 
16 Ibid.  
17 GDUFA III commitment letter at 17. 
18 21 CFR 314.110(c)(1). 
19 21 CFR 314.110(c)(2). 
20 Ibid. 
  4  Contains Nonbinding Recommendations 
 
  For an applicant submitting a request for an additional extension, the reason why 
o
it was unable to respond to the deficiencies identified in the CRL within the time 
period FDA granted in the previous extension  
 
  Information about the additional work that needs to be performed before the 
o
applicant can respond to the CRL 
 
  Evidence of progress being made toward the completion of work needed to respond to the 
deficiencies in the CRL (e.g., information demonstrating that the ANDA applicant is 
working to address the deficiencies) 
 
  The amount of additional time the applicant is requesting 
 
D.  Evaluation of a Request for an Extension to Respond to a CRL 
 
FDA will evaluate requests for an extension of time to respond to a CRL and will grant any 
requests that FDA determines are reasonable.21  In addition to the information provided by the 
applicant when submitting a request for an extension, below is a non-exhaustive list of factors 
that FDA generally intends to consider in determining whether such requests are reasonable:22   
 
  The number of, length, and reason(s) for any previously granted extension(s) for the 
ANDA  
 
  The number and types of deficiencies identified in the CRL (e.g., whether the 
deficiencies were originally classified as major or minor in the CRL)23  
 
  Extenuating factors that are outside of the control of the applicant that impact the 
applicants ability to respond to the CRL (e.g., if the applicant is unable to obtain the 
RLD24 and is attempting to procure the product samples under CREATES25)   
 
21 21 CFR 314.110(c). 
22 The factors identified in this guidance are specific to evaluating requests for an extension to respond to a complete 
response letter for an ANDA and were developed in consideration of the Office of Generic Drugs program needs.  
Other offices within CDER may consider different factors in determining whether an extension request is 
reasonable.   
23 See the guidance for industry ANDA Submissions  Amendments to Abbreviated New Drug Applications Under 
GDUFA (July 2018).   
24 As used here, the term RLD may also refer to the reference standard (RS) in cases where the RLD is no longer 
marketed. The RS is the drug product selected by FDA that an applicant seeking approval of an ANDA must use in 
conducting any bioequivalence study in humans for approval of the ANDA.  21 CFR 314.3(b). Ordinarily, the RS 
selected by FDA will be the RLD.  Where the RLD has been withdrawn from sale (for reasons other than safety and 
effectiveness), FDA generally will select a previously approved ANDA that referred to the RLD as the RS. 
25 See Public Law 116-94 (Further Consolidated Appropriations Act, 2020, enacting Division N, Title I, Subtitle F, 
Section 610Actions for Delays of Generic Drugs and Biosimilar Biological Products (Dec. 20, 2019)).  The 
provisions of this law related to access to product samples were codified at 21 U.S.C. 355-2 and 355-1(l).  For 
information on access to product samples, see the draft guidance for industry How To Obtain a Covered Product 
Authorization (September 2022).  When final, this guidance will represent the FDAs current thinking on this topic.  
  5  Contains Nonbinding Recommendations 
 
 
  Other public health reasons necessitating an extension 
 
See Appendix A for examples of factors that FDA could consider as the basis for concluding that 
an applicants request for an extension of time to respond to a CRL is reasonable.    
 
E.  Withdrawal of an ANDA 
 
Under 21 CFR 314.110(c), FDA will grant any reasonable request for an extension of time to 
respond to a CRL.  If FDA determines that a request for an extension of time (i.e., a first or 
subsequent extension of time) to respond to a CRL is not reasonable, FDA will notify the 
applicant in writing of that determination.26  The applicant will have 30 days from the date of the 
notification denying the extension request to respond in writing explaining why the ANDA 
should not be withdrawn.27  If the applicant does not respond to FDAs denial of the extension 
request within 30 days, and the time for responding to the CRL has elapsed, FDA will deem the 
ANDA withdrawn and notify the applicant of the withdrawal in writing.28  If the applicant 
responds to that notification within 30 days and requests an extension of time that includes 
information not previously considered by the Agency, FDA will evaluate that request with the 
new information and will grant any reasonable request for an extension.29  However, if FDA 
determines that the request for an extension is not reasonable, FDA will deem the ANDA 
withdrawn and notify the applicant of the withdrawal in writing.30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
26 See 21 CFR 314.110(c). 
27 21 CFR 314.110(c)(2). 
28 21 CFR 314.110(c)(2). 
29 Ibid. 
30 Ibid. 
  6  Contains Nonbinding Recommendations 
 
 
 
 
 
 
Appendix A 
 
This Appendix provides examples of factors that FDA could consider as the basis for concluding 
that an applicants request for an extension of time to respond to a CRL is reasonable.  This is a 
non-exhaustive list.  FDA will make such determinations based on the facts and circumstances of 
each individual case and will grant any reasonable request for an extension. 
 
  A national or global public health emergency (e.g., COVID-19) delayed the initiation of 
studies needed to address deficiencies identified in the CRL. 
  The ANDA applicant and/or active pharmaceutical ingredient (API) manufacturer are 
conducting an ongoing risk assessment for impurities in the drug product and/or API. 
  The ANDA applicant is conducting an ongoing analytical assessment of 
extractables/leachables. 
  The ANDA applicant is unable to procure the API from the API manufacturer. 
  The ANDA applicant is unable to obtain the RLD and is attempting to procure the 
product samples under CREATES. 
  The RLD has reformulated and the ANDA applicant needs to conduct new 
bioequivalence (BE) studies.   
  The ANDA applicant chooses to conduct new BE studies based on the deficiencies 
identified in the CRL and needs to manufacture one or more new test product batches to 
conduct the BE studies. 
  The ANDA applicant is transferring production to a new manufacturing facility. 
  The ANDA applicant is continuing to address deficiencies identified during a recent 
facility inspection. 
 
  7