Chemotherapy-Induced 
Nausea and Vomiting: 
Developing Drugs for 
Prevention 
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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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) Mary Chung at 301-796-0260. 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
May 2021 
Clinical/Medical 
43666450dft.docx 
05/14/21   
Chemotherapy-Induced 
Nausea and Vomiting: 
Developing Drugs for 
Prevention 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
May 2021 
Clinical/Medical 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION ........................................................................................... 1 
II.  BACKGROUND.............................................................................................. 2 
III.  DEVELOPMENT PROGRAM ....................................................................... 3 
A.  Trial Population ................................................................................................. 3 
B.  Trial Design ....................................................................................................... 4 
C.  Efficacy Considerations ...................................................................................... 4 
1. Efficacy Assessments ............................................................................................ 4 
2. Statistical Considerations...................................................................................... 5 
D.  Clinical Outcome Assessments ............................................................................ 6 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Chemotherapy-Induced Nausea and Vomiting: 
2  Developing Drugs for Prevention 
3  Guidance for Industry1 
4   
5   
6   
7   
8  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
9  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
10  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
11  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
12  for this guidance as listed on the title page. 
13   
14   
15   
16   
17  I.  INTRODUCTION 
18   
19  The purpose of this guidance is to help sponsors in the clinical development of drugs for the 
20  prevention of chemotherapy-induced nausea and vomiting (CINV) in adults.2  Specifically, this 
21  guidance addresses FDAs current recommendations on clinical trials for drugs being developed 
22  under Section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C.  355) and 21 CFR 
23  Parts 312 and 314 for the prevention of CINV and considerations for eligibility criteria, trial 
24  design features, efficacy evaluations, and clinical outcome assessments.3  
25   
26  This guidance does not address the development of drugs for the treatment of CINV or the 
27  prevention or treatment of nausea and vomiting unrelated to the administration of 
28  chemotherapeutic agents.4  
29   
30  The contents of this document do not have the force and effect of law and are not meant to bind 
31  the public in any way, unless specifically incorporated into a contract.  This document is 
32  intended only to provide clarity to the public regarding existing requirements under the law. 
 
1 This guidance has been prepared by the Division of Gastroenterology in the Center for Drug 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 therapeutic biological 
products unless otherwise specified. 
 
3 In addition to consulting guidances, sponsors are encouraged to contact the Division to discuss specific issues that 
arise during the development of drugs for the treatment of CINV. 
 
4 This guidance includes recommendations for development programs for drugs for the prevention of CINV for 
patients receiving single-day antineoplastic therapy.  FDA recommends that sponsors assess the efficacy, dosing, 
and safety of drugs for the prevention of CINV in patients receiving multiday antineoplastic therapy independently 
from those receiving single-day regimens. 
 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
33  FDA guidance documents, including this guidance, should be viewed only as recommendations, 
34  unless specific regulatory or statutory requirements are cited.  The use of the word should in 
35  Agency guidances means that something is suggested or recommended, but not required. 
36   
37   
38  II.  BACKGROUND 
39   
40  CINV has been identified by cancer patients as the adverse effect of treatment with the highest 
41  impact on their quality of life.  An estimated 80 percent of patients undergoing chemotherapy 
42  experience CINV.  CINV can cause decreased appetite, compromised nutrition, and dehydration 
43  that can progress to metabolic derangements.  Inadequate control of CINV can lead to patient 
44  noncompliance or withdrawal from antineoplastic therapies, directly impacting overall 
45  prognosis. 
46   
47  With the known burden and potential implications of these symptoms, providing preventative 
48  treatment for CINV is the standard of care for patients undergoing chemotherapy with 
49  moderately or highly emetogenic agents.  A combination of drugs from multiple therapeutic 
50  classes is frequently required to achieve optimal prevention of CINV, and recommendations for 
51  preventative treatment regimens are available from several professional organizations, including 
52  the American Society of Clinical Oncology (ASCO).5,6 
53   
54  ASCO guidelines define chemotherapy regimens (including combination regimens) associated 
55  with a 90 percent or higher incidence of nausea and vomiting in the absence of antiemetic 
56  prophylaxis as highly emetogenic chemotherapy (HEC) and regimens associated with a 30 to 90 
57  percent incidence of vomiting as moderately emetogenic chemotherapy (MEC).  FDA 
58  recommends that sponsors use these definitions of HEC and MEC when designing drug 
59  development programs. 
60   
61  CINV is further classified by the onset of symptoms relative to the timing of chemotherapy 
62  administration into acute phase (onset 0 through 24 hours) and delayed phase (onset >24 
63  through 120 hours).  The overall phase of CINV is defined as symptoms that are present from 0 
64  to 120 hours following chemotherapy administration. 
65   
66   
 
5 Hesketh, PJ, MG Kris, E Basch, K Bohlke, SY Barbour, RA Clark-Snow, MA Danso, K Dennis, LL Dupuis, SB 
Dusetzina, C Eng, PC Feyer, K Jordan, K Noonan, D Sparacio, MR Somerfield, and GH Lyman, 2017, Antiemetics: 
American Society of Clinical Oncology Clinical Practice Guideline Update, J Clin Oncol, 35(28):32403261. 
 
6 For additional preventative treatment guidelines, see the National Comprehensive Cancer Network, available at 
https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf; the Multinational Association of Supportive 
Care in Cancer Guidelines, available at https://www.mascc.org/clinical-guidelines; and the European Society for 
Medical Oncology, available at https://www.esmo.org/guidelines/supportive-and-palliative-care/prevention-of-
chemotherapy-and-radiotherapy-induced-nausea-and-vomiting. 
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
67  III.  DEVELOPMENT PROGRAM 
68   
69  A.  Trial Population 
70   
71  Sponsors developing drugs for the prevention of CINV should consider the following when 
72  selecting clinical trial populations:  
73   
74    To support an indication for the prevention of acute, delayed, or acute and delayed nausea 
75  and vomiting associated with HEC, patients should receive chemotherapy classified as 
76  HEC by the ASCO guidelines, such as cisplatin. 
77   
78    Although ASCO reclassified anthracycline/cyclophosphamide (AC) chemotherapies from 
79  MEC to HEC in 2011, AC chemotherapy has been demonstrated to be less emetogenic 
80  than other agents classified as HEC (i.e., cisplatin).  FDA does not consider data obtained 
81  solely from AC chemotherapybased trials adequate to demonstrate substantial evidence 
82  of effectiveness in patients receiving other HEC regimens.  Programs including patients 
83  treated with AC chemotherapy should include multiplicity-controlled analyses of the 
84  primary and secondary endpoints limited to patients receiving non-AC HEC (per ASCO 
85  guidelines) to support a demonstration of efficacy for patients receiving HEC.  
86   
87    Available data show that drugs demonstrated to be effective at preventing CINV in a 
88  population receiving HEC are also effective at preventing CINV in patients receiving 
89  MEC.  Therefore, FDA may consider approving an indication for the prevention of CINV 
90  in patients receiving MEC based on sufficient data to support the safe use of the drug in 
91  the MEC population, together with demonstration of effectiveness in adequate and well-
92  controlled trials in patients receiving HEC. 
93   
94    If an indication for the prevention of CINV in patients receiving MEC is being sought 
95  independently, the trial population or populations should receive chemotherapeutic agents 
96  classified as MEC by the ASCO guidelines. 
97   
98    Patients with brain metastases should be included in early drug development trials to 
99  facilitate the collection of data to inform the development of eligibility criteria in later-
100  phase trials.  In cases where there is a strong rationale for exclusion, the rationale should 
101  be described in the trial protocol.7 
102   
 
7 For additional recommendations, see the guidance for industry Cancer Clinical Trial Eligibility Criteria: Brain 
Metastases (July 2020).  We update guidances periodically.  To make sure you have the most recent version of a 
guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents. 
 
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
103  B.  Trial Design8 
104   
105  Sponsors developing drugs for the prevention of CINV should consider the following when 
106  designing clinical trials: 
107   
108    Patients should receive standard of care background antiemetic therapy in accordance 
109  with the ASCO guidelines.  These regimens should be protocol-specified, standardized, 
110  and given to all patients in both treatment groups to facilitate the interpretation of the test 
111  drugs safety and effectiveness. 
112   
113    FDA recommends a randomized, double-blind, placebo-controlled trial design for 
114  sponsors that intend to demonstrate superiority of their drug added to standard of care 
115  compared with standard of care alone.  
116   
117    FDA recommends a randomized, double-blind, active comparator trial design for 
118  sponsors that intend to demonstrate noninferiority or superiority to an approved therapy.9  
119  Such a trial should include the following arms: 
120   
121    Active Comparator: Standard of care antiemetic prophylaxis (drugs from two to four 
122  classes as recommended by ASCO) 
123   
124    Investigational Treatment: Standard of care antiemetic prophylaxis (drugs from two 
125  to four classes as recommend by ASCO) with the investigational product replacing 
126  the drug of the same class used in the comparator arm 
127   
128    Permitted rescue medications and their administration schedule should be protocol-
129  specified and standardized.  
130   
131  C.  Efficacy Considerations 
132   
133  Sponsors developing drugs for the prevention of CINV should consider the following: 
134   
135  1.  Efficacy Assessments 
136   
137    To establish efficacy for the prevention of CINV, FDA recommends the following: 
138   
139    A primary efficacy endpoint of complete response, defined as no vomiting and no use 
140  of rescue antiemetic medication 
141   
 
8 For additional recommendations and considerations for clinical trial populations, see the guidance for industry 
Enhancing the Diversity of Clinical Trial Populations  Eligibility Criteria, Enrollment Practices, and Trial 
Designs (November 2020). 
 
9 For additional recommendations and considerations for noninferiority clinical trial designs, see the guidance for 
industry Non-Inferiority Clinical Trials to Establish Effectiveness (November 2016).   
 
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
142    A secondary endpoint of the absence of nausea, defined as no nausea and no use of 
143  rescue antiemetic medication10 
144   
145    Sponsors should prespecify the acute phase (0 through  24 hours), the delayed phase 
146  (>24 through  120 hours), or acute and delayed phases to define the period or periods 
147  for efficacy endpoint assessments, depending on the mechanism of action of the drug and 
148  when the primary treatment effects are anticipated. 
149   
150    Sponsors may include a secondary endpoint of the assessment of efficacy in the overall 
151  phase (onset within 0 through  120 hours).  FDA does not recommend sponsors select 
152  the overall phase for primary efficacy assessments, as drugs are often found to be 
153  effective for either acute or delayed onset CINV, and this information is needed to inform 
154  optimal use. 
155   
156    To support the efficacy of a drug for repeat courses of chemotherapy, FDA recommends 
157  that efficacy be demonstrated during at least four chemotherapy cycles. 
158   
159  2.  Statistical Considerations 
160   
161    FDA recommends sponsors analyze the primary endpoint (i.e., a binary endpoint defined 
162  as no vomiting and no use of rescue antiemetic medication) and secondary endpoint (i.e., 
163  a binary endpoint defined as no reported nausea and no use of rescue antiemetic 
164  medication) by evaluating the difference in the proportions of responders across 
165  treatment arms.  
166   
167    To gain precision in evaluating overall treatment effects, FDA recommends that 
168  statistical analyses adjust for patient characteristics at baseline that may impact efficacy 
169  outcomes, (e.g., younger age, female sex, a history of morning sickness, history of no or 
170  low use of alcohol, history of previous chemotherapy, the presence of central nervous 
171  system lesions, and history of motion sickness).  Sponsors should also consider exploring 
172  subgroup analyses and potential treatment interactions based on these factors. 
173   
174    Sponsors should prespecify the approach to ensure tight control of type I error rate when 
175  testing multiple endpoints (i.e., primary and secondary endpoints) that are clinically 
176  meaningful and for which labeling claims may be of interest. 
177   
178    If treatment effects are anticipated in both the acute and the delayed phases, these 
179  analyses should also be appropriately controlled for multiplicity. 
180   
181   
182   
183   
 
10 Demonstrating significant treatment effect on the primary endpoint of complete response (no vomiting and no use 
of rescue antiemetic medication) in the absence of a significant treatment effect on the secondary endpoint (no 
nausea and no use of rescue antiemetic medication) may not be sufficient to support an indication for the prevention 
of the nausea component of the CINV indication. 
5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
184  D.  Clinical Outcome Assessments 
185   
186  Sponsors developing drugs for the prevention of CINV should consider the following when 
187  using clinical outcome assessments (e.g., patient-reported outcome and observer-reported 
188  outcome instruments): 
189   
190    FDA recommends collecting data related to the severity of the patients nausea at its 
191  worst during the recall period (e.g., using a verbal rating scale with response options such 
192  as none, mild, moderate, and severe), assessing frequency and/or duration of nausea, and 
193  assessing impacts of nausea on the patients daily living and functioning.  The design of 
194  the instrument selected (including the specific response options in the questions included) 
195  should be informed by qualitative data from patients to demonstrate that the measurement 
196  strategy adequately captures patients experiences with nausea.11   
197   
198    Sponsors should use instruments with daily assessments (e.g., using a recall period of the 
199  past 24 hours), and respondents should complete the instruments at the same time each day 
200  (e.g., in the evening before bedtime).  Instruments should measure the primary endpoint of 
201  complete response (i.e., no vomiting and no use of rescue medication) and the secondary 
202  endpoint of no nausea and no use of rescue antiemetic medication, using either the same 
203  or different instruments for each endpoint.  
204   
205    Sponsors should seek FDA input about selecting or developing appropriate instruments 
206  and endpoints for their drug development program as early as possible and at important 
207  milestones throughout the drug development process. 
 
11 For additional recommendations, see the guidance for industry, Food and Drug Administration staff, and other 
stakeholders Patient-Focused Drug Development: Collecting Comprehensive and Representative Input (June 2020).  
For general recommendations for patient-reported outcome assessments (as well as information relevant to other 
clinical outcome assessments) and the document to be provided to FDA for review, see the guidance for industry 
Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims (December 
2009).  
6