Considerations for 
Rescinding 
Breakthrough Therapy 
Designation 
Guidance for Industry 
 
 
 
 
 
DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to https://www.regulations.gov.  Submit written 
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061, Rockville, MD  20852.  All comments should be identified with the 
docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact (CDER) Dat Doan, 240-402-8926, or 
(CBER) Office of Communication, Outreach and Development, 800-835-4709 or 240-402-8010. 
 
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) 
Oncology Center of Excellence (OCE) 
 
June 2022 
Procedural 
43135914dft.docx 
06/21/2022   
Considerations for 
Rescinding 
Breakthrough Therapy 
Designation 
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 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
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/guidance-compliance-regulatory-information/guidances-drugs  
and/or 
Office of Communication, Outreach and Development  
Center for Biologics Evaluation and Research 
 Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 71, Room 3128 
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) 
Oncology Center of Excellence (OCE) 
 
 
 June 2022 
Procedural 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  GENERAL CONSIDERATIONS FOR RESCINDING BREAKTHROUGH 
THERAPY DESIGNATION ....................................................................................................... 2 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Considerations for Rescinding Breakthrough Therapy Designation  
2  Guidance for Industry1 
3   
4   
5  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
6  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
7  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
8  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
9  for this guidance as listed on the title page.   
10   
11   
12   
13   
14  I.  INTRODUCTION  
15   
16  This guidance explains how, during its evaluation of a drug2 development program, FDA may 
17  consider whether to rescind a breakthrough therapy designation (BTD).  This guidance is 
18  consistent with, and supplements, the information on BTD contained in the guidance for industry 
19  Expedited Programs for Serious ConditionsDrugs and Biologics (May 2014)3 and other BTD 
20  policies and procedures of the Center for Drug Evaluation and Research (CDER)4 and the Center 
21  for Biologics Evaluation and Research (CBER).5 
22     
23  The contents of this document do not have the force and effect of law and are not meant to bind 
24  the public in any way, unless specifically incorporated into a contract.  This document is 
25  intended only to provide clarity to the public regarding existing requirements under the law.  
26  FDA guidance documents, including this guidance, should be viewed only as recommendations, 
27  unless specific regulatory or statutory requirements are cited.  The use of the word should in 
28  Agency guidances means that something is suggested or recommended, but not required. 
29   
 
1 This guidance has been prepared by the Oncology Center of Excellence (OCE) and the Center for Drug Evaluation 
and Research in cooperation with the Center for Biologics Evaluation and Research at the Food and Drug 
Administration.  
 
2 For the purposes of this guidance, all references to drugs include both human drugs and biological products unless 
otherwise specified. 
 
3 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.  
 
4 See CDERs Manual of Policies and Procedures (MAPP) 6025.6 Good Review Practice:  Management of 
Breakthrough Therapy-Designated Drugs and Biologics.  CDER MAPPs are available at 
https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/cder-manual-policies-procedures-mapp. 
 
5 See CBERs Standard Operating Policy and Procedure (SOPP) 8212 Version 2 Management of Breakthrough 
Therapy-Designated Products:  Sponsor Interactions and Status Assessment Including Rescinding.  CBER SOPPs 
are available at https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-
biologics/biologics-procedures-sopps.  
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
30   
31  II.  BACKGROUND 
32   
33  Section 506(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 356(a)) 
34  provides for the granting of BTD if the drug is intended, alone or in combination with 1 or more 
35  other drugs, to treat a serious or life-threatening disease or condition and preliminary clinical 
36  evidence indicates that the drug may demonstrate substantial improvement over existing 
37  therapies on 1 or more clinically significant endpoints, such as substantial treatment effects 
38  observed early in clinical development.  The BTD program is intended to facilitate and expedite 
39  the development of those drugs that receive designation and involves a resource commitment 
40  from FDA to provide early and frequent advice, conduct multidisciplinary meetings involving 
41  senior managers, and when appropriate, expedite the review of resultant marketing applications.  
42  Thus, it is important that available evidence continues to fulfill the standards for BTD. 
43   
44  Breakthrough therapy designation applies to a drug (either alone or in combination with other 
45  drugs) and the specific use for which it is being studied.  The information supporting the granting 
46  of BTD for a particular drug may change over time.  Some drugs that appear promising in early 
47  development may not be shown to be safe or effective in later trials, or the magnitude of a 
48  treatment effect suggested by early development may not be observed in later stages of 
49  development.  Accordingly, given the resource-intensive nature of the BTD program, and in 
50  keeping with the Agencys authority to grant BTD only to drugs that meet the legal criteria, FDA 
51  periodically assesses whether designated products continue to meet the criteria for BTD.  If the 
52  designation is no longer supported by subsequent data, FDA may rescind the designation.6 
53   
54   
55  III.  GENERAL CONSIDERATIONS FOR RESCINDING BREAKTHROUGH 
56  THERAPY DESIGNATION 
57   
58  Early clinical data, including evidence based upon robust pharmacodynamic endpoints, are 
59  typically used to support a BTD.  Subsequent to granting BTD, information may become 
60  available such that the evidence no longer shows that the drug satisfies the BTD criteria.  For 
61  example, a BTD may be rescinded for reasons such as:  
62   
63  1.  A different drug is approved to treat the unmet need that informed the rationale for 
64  granting BTD.  As a result of this new therapy, the BTD drug no longer meets the BTD 
65  criteria regarding substantial improvement over existing available therapies.7  Note that 
 
6 FDA follows the processes described in MAPP 6025.6 and SOPP 8212 for rescinding BTD. 
 
7 Available therapy (and the terms existing treatment and existing therapy), as used herein, reflect the meaning of the 
term as discussed in the guidance for industry Expedited Programs for Serious ConditionsDrugs and Biologics 
(May 2014); those terms should generally be understood to refer to therapy that is approved or licensed in the United 
States for the same indication being considered for the new drug, and that is still relevant to the standard of care.  In 
exceptional cases, a treatment that is not approved for the indicated use may be considered available therapy if the 
safety and effectiveness of the use is supported by compelling evidence, including extensive evidence in the 
published literature.  For further discussion of available therapy, see the guidance for industry Expedited Programs 
for Serious ConditionsDrugs and Biologics, pp. 23. 
 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
66  another drug approved under accelerated approval generally will not be considered 
67  sufficient to lead to rescinding BTD. 
68   
69  2.  Emerging data for the designated drug no longer support a finding that preliminary 
70  clinical evidence indicates that the drug may demonstrate substantial improvement over 
71  existing therapies.8   
72   
73  3.  The designated drugs sponsor is no longer pursuing the drugs development program for 
74  the use that was the basis for BTD.   
75   
76  For example, rescinding a BTD may be warranted if a phase 3 trial intended to definitively show 
77  the designated drugs effect fails to meet its primary endpoint, or the extent of benefit is more 
78  modest such that the trial does not indicate that the drug may demonstrate a substantial 
79  improvement over available therapy.  The emergence of additional safety information that alters 
80  the benefit-risk assessment of the designated product may also support a decision to rescind 
81  BTD.   
82   
83  In assessing whether the criteria for BTD continue to be met, FDA typically gives greater weight 
84  to trials that are conducted in larger populations, use a well-understood and widely accepted, 
85  well-constructed clinical endpoint, and incorporate certain design features (e.g., randomization, 
86  blinding).  Thus, the quality of evidence available may impact FDAs decision-making. 
87   
88  In certain circumstances, FDA may decide not to rescind BTD designation, even if subsequent 
89  results appear not to support the evidence on which BTD was based.  For example, if initial data 
90  were promising, and there are significant issues with the conduct and design of a subsequent 
91  study, the subsequent study may be given less weight in assessing whether the criteria for BTD 
92  are still met.  However, if the evidence available from multiple well-designed studies reflect an 
93  inconsistent picture of clinical benefit, the assessment of whether the criteria for BTD continue 
94  to be met may become more challenging.  For example, if a trial does not demonstrate 
95  statistically significant improvement in the primary endpoint being studied, but shows a 
96  favorable trend on a secondary clinical endpoint of interest, then the trial might still be consistent 
97  with FDAs determination that there is preliminary clinical evidence9 to support BTD.  In such 
98  circumstances, maintaining the drugs BTD may be warranted, especially if the preliminary 
99  clinical evidence10 that led to the original BTD was strong.  The decision whether to maintain 
100  or revoke BTD in such cases will depend on the facts specific to that drug development program. 
101   
102  This guidance document provides general considerations, and sponsors are encouraged to discuss 
103  specifics with FDA concerning evolving information and circumstances surrounding BTD for a 
104  particular drug.  
 
8 See section 506(a) of the FD&C Act. 
 
9 Ibid. 
 
10 Ibid. 
  3