Bladder Cancer: 
Developing Drugs and 
Biologics for Adjuvant 
Treatment 
Guidance for Industry 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Oncology Center of Excellence (OCE) 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
June 2022 
Clinical/Medical  Bladder Cancer: 
Developing Drugs and 
Biologics for Adjuvant 
Treatment  
Guidance for Industry 
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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 
Oncology Center of Excellence (OCE) 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
June 2022 
Clinical/Medical  Contains Nonbinding Recommendations
TABLE OF CONTENTS 
I.  INTRODUCTION............................................................................................................. 1
II.  BACKGROUND ............................................................................................................... 1
III.  RECOMMENDATIONS .................................................................................................. 2
A.  Trial Eligibility Criteria ................................................................................................................ 2
B.  Choice of Comparator ................................................................................................................... 3
C.  Imaging Assessments ..................................................................................................................... 3
D.  Determination of Disease Recurrence .......................................................................................... 4
E.  Trial Analysis ................................................................................................................................. 4
F.   Interpretation of Trial Results ...................................................................................................... 5 Contains Nonbinding Recommendations 
 
Bladder Cancer: Developing Drugs and Biologics for Adjuvant 
Treatment  
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 staff responsible for this guidance as listed on the 
title page. 
I.  INTRODUCTION 
This guidance provides recommendations to sponsors regarding the development of drugs and 
biological products2 regulated by CDER and CBER for the adjuvant treatment of muscle-
invasive bladder cancer. The guidance includes recommendations regarding eligibility criteria, 
choice of comparator, follow-up imaging assessments, determination of disease recurrence, 
analyses of disease-free survival (DFS), and interpretation of trial results. Although FDA may 
consider endpoints other than DFS for the adjuvant treatment of muscle-invasive bladder cancer, 
this guidance is focused on clinical trials with DFS as the primary efficacy endpoint. 
The contents of this document do not have the force and effect of law and are not meant to bind 
the public in any way, unless specifically incorporated into a contract. This document is intended 
only to provide clarity to the public regarding existing requirements under the law. FDA 
guidance documents, including this guidance, 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 
Significant variability exists in the design, conduct, and analysis of trials for the adjuvant 
treatment of bladder cancer, including the eligibility criteria, radiological disease assessments, 
the definition of disease recurrence, and the date used to define the DFS endpoint. Consistency in 
these aspects within and across trials may facilitate interpretation of trial results. These issues 
1 This guidance has been prepared by the Oncology Center of Excellence (OCE), Center for Drug Evaluation and 
Research (CDER), and Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration.   
2 For the purposes of this guidance, references to drugs include drugs approved under section 505 of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 355) and biological products licensed under section 351 of the Public 
Health Service Act (42 U.S.C. 262). 
1 Contains Nonbinding Recommendations 
 
were discussed at an FDA-National Cancer Institute (NCI) public workshop held on November 
28, 2017.3, 4
III.  RECOMMENDATIONS 
A.  Trial Eligibility Criteria 
  Patients with predominant urothelial carcinoma (UC) histology who have a component of 
variant histology should be included. Detailed pathology information including histology 
should be prospectively captured.  
  We encourage the enrollment of patients with microscopic positive margins without gross 
residual disease but sponsors should account for potential heterogeneity with regard to 
treatment effect and risk for recurrence. 
  Patients with invasive upper-tract UC should be included. 
  See section III.C for recommendations regarding imaging assessments relevant to 
eligibility criteria. 
  If patients who received neoadjuvant therapy prior to study entry are eligible, eligibility 
criteria should ensure that such patients received adequate neoadjuvant therapy, 
consistent with current standard of care. Eligibility criteria for patients who have not 
received standard of care neoadjuvant treatment should be based on post-cystectomy 
pathologic stage and should be pre-specified in the protocol.  
  Eligibility criteria defining cisplatin ineligibility that includes: Eastern Cooperative 
Oncology Group performance status (ECOG-PS) 2, creatinine clearance (CrCl) < 60 
mL/min, grade  2 hearing loss, grade  2 neuropathy, or New York Heart Association 
(NYHA) class III heart failure, should be pre-specified.5
  The protocol should require documentation of tumor stage, grade, extent, and the number 
of lymph nodes sampled at the time of cystectomy to ensure eligibility criteria are met. 
Case report forms should be designed to capture this information. 
3 Apolo AB, Milowsky MI, Kim L, et.al., 2019, Eligibility and Radiologic Assessment in Adjuvant Clinical Trials in 
Bladder Cancer, JAMA Oncol, 5(12):1790-1798.   
4 For information regarding drug development for bacillus Calmette-Guerin (BCG)-unresponsive, nonmuscle-
invasive bladder cancer, see the guidance for industry BCG-Unresponsive Nonmuscle Invasive Bladder Cancer: 
Developing Drugs and Biologics for Treatment (February 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. 
5 Galsky MD, Hahn NM, Rosenberg J, et al., 2011, Treatment of Patients with Metastatic Urothelial Cancer Unfit 
for Cisplatin-Based Chemotherapy, JCO, 29(17):2432-2438. 
2 Contains Nonbinding Recommendations 
 
  Patients with residual or recurrent malignant disease should be excluded. 
  Any lesions that could possibly represent residual or recurrent bladder cancer on 
o
imaging should be biopsied prior to enrollment, if safe and feasible, to assess for 
the presence of malignant disease and to document eligibility. 
  When a biopsy is not safe or feasible, it may be necessary to use imaging to 
o
establish absence of residual or recurrent disease at baseline prior to enrollment to 
document eligibility. The radiological definition of no evidence of disease 
should be prespecified in the protocol. For example, for patients entering these 
trials with enlarged lymph nodes or sub-centimeter lesions in the visceral organs 
that are not amenable to biopsy, the protocol should contain criteria concerning 
the size or other characteristics of these lesions that establish absence of disease 
for the purpose of determining eligibility in the trial.  
  A large number of discrepancies between investigator and blinded independent central 
review (BICR) with respect to presence of disease on baseline imaging may interfere 
with interpretation of results. Consider determination of eligibility based on absence of 
disease by BICR.  
B.  Choice of Comparator  
The appropriate choice of comparator should be discussed with the FDA prior to study 
initiation and should be consistent with standards of care and with practice patterns in the 
U.S.  
C.  Imaging Assessments 
  The protocol should specify acceptable methods of imaging acquisition, display, and 
radiological interpretation technique for use in determination of DFS. The protocol 
should specify using the same modality throughout the duration of the trial for an 
individual patient.  
  Initial imaging studies should be timed to allow for stabilization of post-surgical imaging 
and is recommended to be completed within 4 weeks prior to trial enrollment. 
  Imaging assessment frequency should be the same on all treatment arms as asymmetrical 
frequencies may bias the assessment of DFS. The anticipated magnitude of effect on DFS 
necessary to demonstrate clinical benefit should be considered in planning the frequency 
of imaging assessments. The magnitude of DFS improvement should be greater than the 
imaging frequency for DFS to be interpretable.  
3 Contains Nonbinding Recommendations 
 
D.  Determination of Disease Recurrence  
  We recommend the determination of disease recurrence for DFS be based on the 
assessment by a BICR.  If it is based on investigator assessment, it should include a BICR 
audit.  
  Radiological findings suggestive of disease recurrence should be supported by tumor 
biopsies to confirm malignant disease, whenever safe and feasible. 
  The radiological definition of recurrence by site (e.g., tumor bed, lymph nodes, bone 
metastases, visceral disease) should be prespecified, in case biopsy is not safe or feasible, 
to confirm recurrence. The definition should include the location, size, and the number of 
lesion(s) that define radiological recurrence. The definition should be applied uniformly 
by investigators and the BICR to ensure consistency in criteria for recurrent disease in the 
absence of histologic confirmation.  
  The method for assigning date of recurrence should be prespecified and consistently 
applied. For example,  
  When both an image and biopsy document recurrence, the earlier date should be 
o
used for date of recurrence. 
  When confirmatory imaging is required to document disease recurrence in the 
o
absence of biopsy, the date of recurrence should be the date the lesion(s) was first 
identified.  
  New high-grade non-muscle-invasive tumors and all new muscle-invasive bladder cancer 
tumors that develop in the remaining urothelium following resection should be DFS-
defining events. The designation of all other non-muscle invasive tumors as evidence of 
disease recurrence should be discussed with the FDA prior to study initiation and pre-
specified in the protocol. 
  Trials should specify if urine cytology will be used for post-operative surveillance in 
patients who have remaining urothelium, and if so, the specific test and testing interval 
required. Endoscopic surveillance procedures should be pre-specified.  
 E.  Trial Analysis 
  The protocol and statistical analysis plan (SAP) should contain a detailed description of 
the trial assumptions and statistical methods for analysis of DFS and overall survival 
(OS).  
  Procedures should be put in place to minimize missing data, especially for DFS.  
4 Contains Nonbinding Recommendations 
 
  The SAP should specify the primary analysis and sensitivity analyses with different 
censoring rules to evaluate the impact of missing observations, imaging assessment 
frequency, and other factors on the results.  
  Subset analyses should be performed to account for variations in outcomes if sufficient 
numbers of patients with a component of variant histology are enrolled. Those with pure 
non-UC histology (e.g., mixed endocrine/small cell tumors), if included, should be 
analyzed separately. 
F.   Interpretation of Trial Results 
  Interim analyses of DFS to stop for effectiveness are not recommended because immature 
data may lead to over- or underestimation of magnitude of improvement. A study 
designed with interim analyses should be discussed with the Agency prior to initiation. 
Adequate follow-up of the study population prior to efficacy assessment should be 
carefully considered. 
  There is not a single threshold for the magnitude of improvement in DFS required to 
support drug approval. Instead, whether the data support both a conclusion of substantial 
evidence of effectiveness and a favorable benefit-risk evaluation depends on several 
factors including, but not limited to, the trial design (e.g., add-on design, active vs. 
placebo control), trial conduct, study population, magnitude and type of clinical benefit, 
and the toxicity profile observed. 
  Although FDA approval does not require demonstration of an OS benefit, the protocol 
and SAP should include a plan for a formal interim analysis of OS at the time of DFS 
analysis. To support a favorable benefit-risk assessment, this analysis should provide 
assurance that OS is not adversely affected by the treatment. In addition, FDA expects 
continued follow-up to allow conduct of the final OS analysis. 
5