Cancer Clinical Trial 
Eligibility Criteria:  
Patients with Organ 
Dysfunction or Prior or 
Concurrent 
Malignancies 
 
Guidance for Industry
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Oncology Center of Excellence 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
 
July 2020 
Clinical/Medical 
   
Cancer Clinical Trial 
Eligibility Criteria:  
Patients with Organ 
Dysfunction or Prior or 
Concurrent Malignancies 
 
Guidance for Industry 
 
 
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guidances 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration  
Oncology Center of Excellence 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
July 2020 
Clinical/Medical 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  RECOMMENDATIONS .................................................................................................. 3 
A.  Patients with organ dysfunction ................................................................................................... 3 
1. Renal function recommendations ..................................................................................................... 3 
2. Cardiac function recommendations ................................................................................................. 4 
3. Hepatic function recommendations ................................................................................................. 5 
B.  Patients with prior or concurrent malignancy ............................................................................ 5 
  Contains Nonbinding Recommendations 
 
Cancer Clinical Trial Eligibility Criteria:  
Patients with Organ Dysfunction or Prior or Concurrent 
Malignancies 
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 office responsible for this guidance as listed on the 
title page.   
 
 
 
 
I.  INTRODUCTION  
 
This guidance is one in a series of guidances that provide recommendations regarding eligibility 
criteria for clinical trials of drugs or biological products2 regulated by CDER and CBER for the 
treatment of cancer.3 Specifically, this guidance includes recommendations regarding the 
inclusion of patients with organ dysfunction or with prior or concurrent malignancies. This 
guidance is intended to assist stakeholders, including sponsors and institutional review boards, 
responsible for the development and oversight of clinical trials.  
 
A clinical trials eligibility criteria (for inclusion and exclusion) are essential components of the 
trial, defining the characteristics of the study population. Because there is variability in 
investigational drugs and trial objectives, eligibility criteria should be developed taking into 
consideration the mechanism of action of the drug, the targeted disease or patient population, the 
anticipated safety of the investigational drug, the availability of adequate safety data, and the 
ability to recruit trial participants from the patient population to meet the objectives of the 
clinical trial. However, some eligibility criteria have become commonly accepted over time or 
used as a template across trials without clear scientific or clinical rationale. Unnecessarily 
restrictive eligibility criteria may slow patient accrual, limit patients access to clinical trials, and 
                                                 
1 This guidance has been prepared by the Oncology Center of Excellence, 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 and drug and biological products 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). 
3 Topics of the other three guidances are related to eligibility criteria for patients with human immunodeficiency 
virus, hepatitis B virus, or hepatitis C virus infections; for patients with brain metastases; and regarding minimum 
age considerations for inclusion of pediatric patients. 
 
  1  Contains Nonbinding Recommendations 
 
lead to trial results that do not fully represent treatment effects in the patient population that will 
ultimately use the drug.4,5 
 
Broadening cancer trial eligibility criteria can maximize the generalizability of trial results and 
the ability to understand the therapys benefit-risk profile across the patient population likely to 
use the drug in clinical practice and should be considered to avoid jeopardizing patient safety.  
 
Trial design and methodological approaches are important considerations when enrolling a 
broader population and are addressed elsewhere6,7 and are not addressed in this guidance because 
the considerations are not specific to enrolling patients with organ dysfunction or prior or 
concurrent malignancies. 
 
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 guidances means that something is suggested or recommended, but 
not required.  
 
 
II.  BACKGROUND 
 
Patients with organ dysfunction are often excluded from clinical trials, regardless of knowledge 
of the metabolic pathways and excretory routes of the investigational drug. The life-span of the 
general population is increasing and thus includes increasing numbers of patients with co-morbid 
renal disease, cardiac disease, and hepatic dysfunction. Additionally, as life-span of the general 
population increases, a greater number of patients are anticipated to have prior or concurrent 
malignancies. By excluding individuals from cancer clinical trials who have major organ 
dysfunction or previous or concurrent cancers, trial recruitment may favor younger patients, 
which may not be fully representative of the population for whom the drug will be indicated. 
Designing cancer clinical trials that include patients with organ dysfunction and prior or 
concurrent malignancies and including this information in the labeling promotes the safe and 
effective use of these products across a broader patient population likely to use the drug in 
clinical practice. 
 
 
 
                                                 
4 Beaver JA, Ison G, Pazdur R, 2017, Reevaluating Eligibility Criteria- Balancing Patient Protection and 
Participation in Oncology Trials, NEJM, 376:1504-1505.  
5 Kim E, Bruinooge S, Roberts S, et al., 2017, Broadening Eligibility Criteria to Make Clinical Trials More 
Representative: American Society of Clinical Oncology and Friends of Cancer Research Joint Research Statement, 
JCO, 35(33): 3737-3744. 
6 See the draft guidance for industry Enhancing the Diversity of Clinical Trial Populations  Eligibility Criteria, 
Enrollment Practices, and Trial Designs (June 2019). When final, this guidance will represent the FDAs current 
thinking on this topic. 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. 
7 Jin S, Pazdur R, Sridhara R, 2017, Re-Evaluating Eligibility Criteria for Oncology Clinical Trials: Analysis of 
Investigational New Drug Applications in 2015, JCO, 35(33): 3745-3752. 
  2  Contains Nonbinding Recommendations 
 
III.  RECOMMENDATIONS     
 
Thoughtful consideration should be given to the potential inclusion of patients with organ 
dysfunction or prior or concurrent malignancies in cancer clinical trials. The following 
recommendations for eligibility criteria for patients with organ dysfunction in cancer clinical 
trials focus on renal function, cardiac function, and hepatic function. This guidance also includes 
recommendations for eligibility criteria for patients with cancer who have prior or concurrent 
malignancies.  
 
A.  Patients with organ dysfunction 
 
When pharmacokinetics (PK) and major routes of elimination in humans are not well 
understood, it is reasonable to enroll only patients with relatively preserved organ function 
(primarily renal and hepatic) in cancer clinical trials. As data on toxicity, including nonclinical 
and clinical toxicity, PK, and/or pharmacodynamics (PD) become available during drug 
development, protocols should be revised to include patients with compromised organ function 
where safe parameters regarding dosage adjustments have been determined.8 
 
1.  Renal function recommendations 
 
  Eligibility criteria should be based on a contemporary, widely accepted, and 
clinically applicable equation that estimates glomerular filtration rate or a 
measure of glomerular filtration rate rather than an absolute serum creatinine 
concentration. The equation used for a particular patient population should 
remain consistent throughout the investigational drug development process.  
 
  Sponsors should provide adequate justification for the inclusion/exclusion of 
patients with various degrees of renal impairment based on the stage of 
product development, safety profile of the product, understanding of the effect 
of renal impairment on the elimination of the drug, and the safety of study 
procedures in patients with renal impairment.  
 
  Patients with renal impairment should be included in trials of investigational 
drugs when the available nonclinical and clinical data indicate that inclusion 
of patients with renal impairment would not place patients at unreasonable 
risk and/or adequate steps can be taken to mitigate potential risks. When there 
is an expectation that the systemic exposure will increase in patients with 
renal dysfunction, inclusion of such patients may be facilitated by prospective 
dose adjustment to produce similar systemic exposures to those seen in 
patients with relatively preserved kidney function.9 
                                                 
8 Lichtman S, Harvey R, Smit M, et al., 2017, Modernizing Clinical Trial Eligibility Criteria: Recommendations of 
the American Society of Clinical Oncology  Friends of Cancer Research Organ Dysfunction, Prior or Concurrent 
Malignancy, and Comorbidities Working Group, JCO, 35(33): 3753-3759. 
9 Public Workshop: Evaluating Inclusion and Exclusion Criteria in Clinical Trials, Workshop Report, July 2018, 
workshop date April 16, 2018, available at https://www.fdanews.com/ext/resources/files/2018/08-22-18-
FDAsummary.pdf?1534970149 (accessed June 23, 2020). 
  3  Contains Nonbinding Recommendations 
 
  Sponsors should address the need for and timing of studies to evaluate the 
effect of dialysis on drug clearance and the need for dosage adjustment for 
patients on dialysis. 
 
If there is adequate representation of patients with varying degrees of renal impairment, as well 
as data sufficient to adequately describe the impact of renal impairment on PK of the drug, 
population pharmacokinetic (popPK) analyses of data from phase 2 or phase 3 clinical trials may 
be sufficient to characterize the impact of renal function. 
 
2.  Cardiac function recommendations 
 
  Inclusion of patients with cardiovascular dysfunction may be possible when 
available nonclinical and clinical data, including PK and PD data, indicate that 
inclusion of these patients does not expose them to unreasonable risk. 
 
  Patients with significant clinical cardiac abnormalities (e.g., clinical heart 
failure, unstable angina) should be excluded, especially in early-phase studies. 
 
  Inclusion criteria should require investigator assessment of a potential 
participants risk for heart failure with a validated clinical classification 
system (e.g., the New York Heart Association Functional Classification). 
 
  Ejection fraction (EF) measurement: 
 
-  EF measured by either echocardiography or multigated acquisition 
scan is acceptable for determining cardiac EF for eligibility criteria 
purposes.  
 
  QTc Prolongation:10 
 
-  Sponsors should assess the effects of a drug on QTc during early 
clinical development.    
 
-  Sponsors should determine whether a maximum QTc interval is 
necessary as a clinical trial eligibility criterion based on whether there 
is a specific known risk of QTc prolongation, either through non-
clinical (e.g., hERG) or clinical trial data. 
 
 
 
                                                 
10 See the ICH guidance for industry E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic 
Potential for Non-Antiarrhythmic Drugs (October 2005) and the ICH guidance for industry E14 Clinical Evaluation 
of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs  Questions and 
Answers (R3) (June 2017) for additional information regarding QTc prolongation.  
 
  4  Contains Nonbinding Recommendations 
 
3.  Hepatic function recommendations  
 
Unlike other organ systems, liver biochemical testing does not provide sufficient evidence of 
adequate liver drug metabolic function. While estimates of hepatic function that incorporate 
clinical variables as well as functional and laboratory values, such as the Child-Pugh and Model 
for End-Stage Liver Disease scoring systems,11,12 are adopted as markers of hepatic metabolism 
in dedicated PK studies, hepatic metabolism may also be influenced by cancer and inflammation, 
even in the setting of normal scoring. To gauge hepatic drug transformation capacity, pre-
existing liver disease, as well as epidemiological, genetic, environmental, and historical variables 
(e.g., chronic alcohol use and a past history of adverse drug reactions) should be ascertained. 
Impaired hepatic blood flow, in particular when portal hypertension is evident, is critical to 
assessing how the liver metabolizes drugs.  
 
  Inclusion of patients with severe hepatic impairment should be discussed with 
FDA. 
 
  Patients with mild and moderate hepatic impairment13 (defined as the 
equivalent of National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) grade 1 toxicity), as well as those with 
aspartate transaminase (AST) and alanine transaminase (ALT) elevations 
defined as grade 3 by the NCI CTCAE (> 5 to 20 x ULN (upper limit of 
normal)), may be asymptomatic and able to tolerate doses equivalent to 
patients with normal hepatic function. 
 
  Inclusion of patients with mild to moderate hepatic impairment may be 
appropriate when the available nonclinical and clinical data, including PK and 
PD data, indicate that inclusion of these patients does not present an 
unreasonable risk to patients. 
 
B.  Patients with prior or concurrent malignancy  
 
Patients with prior malignancies of the same or different tumor type and patients with concurrent 
malignancies of the same or different tumor type (referred to as prior or concurrent malignancies 
in this guidance) whose natural history or treatment does not have the potential to interfere with 
the safety or efficacy assessment of the investigational drug should generally be eligible for 
enrollment in clinical trials. For example, in initial dose finding or preliminary activity-estimating 
or proof-of-concept studies, patients with a history of prior or concurrent malignancies should not 
be excluded. 
                                                 
11 See the guidance for industry Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data 
Analysis, and Impact on Dosing and Labeling (May 2003).   
12 See the Protocol Template for Organ Dysfunction Studies, updated February 5, 2020 for the NCI criteria, 
available at https://ctep.cancer.gov/protocolDevelopment/templates_applications.htm (accessed June 23, 2020). 
13 Talal AH, Venuto CS, Younis I, 2017, Assessment of hepatic impairment and implications for pharmacokinetics 
of substance use treatment, Clin Pharmacol Drug Dev, 6: 206-212. 
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