Renal Cell Carcinoma: 
 
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  Renal Cell Carcinoma: 
Developing Drugs and 
Biologics for Adjuvant 
Treatment 
   
Guidance for Industry
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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 .......................................................................................... 3
E.  Trial Analysis ................................................................................................................................. 4
F.  Interpretation of Trial Results ...................................................................................................... 4 Contains Nonbinding Recommendations 
 
Renal Cell Carcinoma: 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 renal cell 
carcinoma. 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 renal cell carcinoma, 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 renal cell carcinoma, 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. 
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 
 
These issues were discussed at an FDA-National Cancer Institute (NCI) public workshop held on 
November 28, 2017.3
III.   RECOMMENDATIONS 
A.  Trial Eligibility Criteria 
  Patients with non-clear cell subtypes of renal cell carcinoma, including those with a 
sarcomatoid component should be included. It may be appropriate to study patients with 
non-clear cell histologies in cohorts separately from patients with clear cell histologies to 
account for variations in outcome. 
  We encourage enrollment of patients with microscopically positive soft tissue or vascular 
margins without gross residual disease but sponsors should account for potential 
heterogeneity with regard to treatment effect and risk for recurrence.  
  The protocol should require documentation of tumor stage, nodal and vascular 
involvement, and the number of lymph nodes sampled at the time of nephrectomy to 
ensure that eligibility criteria are met. Case report forms should be designed to capture 
this information. 
  Patients who have undergone radical or partial nephrectomy should be included.  
  See section III.C for recommendations regarding imaging assessments relevant to 
eligibility criteria. 
  Patients with residual or recurrent malignant disease should be excluded. 
  Any lesions on imaging that could possibly represent residual or recurrent kidney 
o
cancer should be biopsied prior to enrollment, if safe and feasible, to assess for 
the presence of malignant disease and to document eligibility. 
  When 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 regarding the 
size or other characteristics of these lesions that establish absence of disease for 
the purpose of determining eligibility in the trial.  
3 Agrawal S, Haas NB, Bagheri M, et. al., 2019, Eligibility and Radiologic Assessment for Adjuvant Clinical Trials 
in Kidney Cancer, JAMA Oncol, 6(1):133-141.  
2 Contains Nonbinding Recommendations 
 
  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 Agency 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.   
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 definition of disease recurrence should address the development of localized disease 
such as a new lesion in the contralateral kidney or at a site away from the original 
3 Contains Nonbinding Recommendations 
 
resection in the ipsilateral kidney after partial nephrectomy in the absence of the 
development of overtly metastatic disease. 
  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 a biopsy, the date of recurrence should be the date the lesion(s) was 
first identified.  
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.  
  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.  
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. 
4