Cancer Clinical Trial 
Eligibility Criteria:  
Brain Metastases 
 
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:  
Brain Metastases 
 
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.  Recommendations for inclusion of patients with treated/stable brain metastases ................... 4 
B.  Recommendations for inclusion of patients with active brain metastases ................................ 4 
C.  Recommendations for inclusion of patients with leptomeningeal metastases .......................... 4 
D.  Recommendations for exclusion of patients with brain metastases .......................................... 4 
E.  Baseline CNS screening ................................................................................................................. 5  Contains Nonbinding Recommendations 
 
Cancer Clinical Trial Eligibility Criteria:  
Brain Metastases 
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.3,4 Specifically, this guidance includes recommendations regarding the 
inclusion of patients with brain metastases. 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 organ dysfunction or with prior or 
concurrent malignancies; and regarding minimum age considerations for inclusion of pediatric patients. 
4 The recommendations in this guidance do not apply to trials designed specifically to assess the safety and efficacy 
of investigational drugs for the treatment of primary brain cancers (e.g., glioblastoma) or brain metastases. 
 
 
  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.5,6,7 
 
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.  
 
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 
 
Every year, approximately 70,000 patients living with cancer in the United States are diagnosed 
with brain metastases. The incidence of brain metastases is increasing in patients with certain 
malignancies such as melanoma, lung cancer, and breast cancer. However, patients with brain 
metastases have historically been excluded from clinical trials due to concerns of poor functional 
status, shortened life expectancy, or increased risk of toxicity.  
 
Clinical trial eligibility criteria have either excluded all patients with known brain metastases or 
restricted enrollment to subgroups of those patients, such as those with treated and clinically 
stable brain metastases. Given the prevalence of brain metastases in patients with cancer, their 
systematic exclusion from clinical trials may result in the assessment of an investigational drugs 
efficacy or safety in a trial population that is not fully representative of the patient population 
that will be prescribed the drug in clinical practice. Designing clinical trials that include patients 
with brain metastases 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. Evidence of clinical efficacy in the subset of patients with brain metastases 
compared to available therapy, with similar efficacy in patients without brain metastases, could 
serve as the basis for one or more expedited programs (i.e., fast track designation, breakthrough 
therapy designation, priority review designation, and/or accelerated approval). Labeling claims 
would depend on the trial design, including the sample size and analysis plan with pre-specified 
hypothesis, and could be included in an indication statement or clinical studies section.  
 
 
 
                                                 
5 Beaver JA, Ison G, Pazdur R, 2017, Reevaluating Eligibility Criteria- Balancing Patient Protection and 
Participation in Oncology Trials, NEJM, 376:1504-1505.  
6 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. 
7 Lin NU, Prowell T, Tan AR, et al., 2017, Modernizing Clinical Trial Eligibility Criteria: Recommendations of the 
American Society of Clinical Oncology  Friends of Cancer Research Brain Metastases Working Group, JCO, 
35(33): 3760-3773. 
  2  Contains Nonbinding Recommendations 
 
III.  RECOMMENDATIONS     
 
Thoughtful consideration should be given to the potential inclusion of patients with brain 
metastases in cancer clinical trials. Patients with brain metastases should be included in clinical 
trials in a way that contributes to a greater understanding of the efficacy and safety profile of the 
investigational drug while maintaining patient safety. Patients with brain metastases should be 
included in early drug development trials to facilitate the collection of data to inform the 
development of eligibility criteria in later-phase trials. In cases where there is a strong rationale 
for exclusion, the rationale should be described in the trial protocol.  
 
The recommendations in this guidance should be carefully considered in the context of disease 
stage (e.g., newly diagnosed, metastatic, refractory), information on the mechanism of action of 
the drug, likelihood of central nervous system (CNS) activity based on pre-existing data, known 
safety profile, available therapies (and risks of forgoing these), and other patient or disease 
factors that may alter the benefits and risks of exposure to the investigational drug. 
 
To mitigate uncertainties about including patients with brain metastases in clinical trials, 
consider enrolling these patients in a separate subgroup within the trial. This strategy allows for 
generation of supportive safety and efficacy data that could be reported and analyzed separately 
from the more primary restricted population that does not include patients with brain metastases 
and may avoid the need for amendments to the protocol or informed consent if futility is 
demonstrated or adverse events are observed in patients with brain metastases. Other strategies to 
mitigate risks include limiting enrollment of patients with active brain metastases to a specific 
number, identifying presence or absence of brain metastases as a stratification factor, designing 
dose-limiting toxicity (DLT) definitions adapted for use in this population, and incorporating 
early stopping rules for excessive toxicity. 
 
Due to the importance of distinguishing drug-related CNS toxicity from symptoms related to 
new or progressive brain metastases, patients with treated/stable, active, or leptomeningeal 
metastases should have CNS imaging at regular intervals. Schedule on-study assessments for 
CNS disease at the same time points as assessments for systemic disease. Any unscheduled 
disease assessments (e.g., due to clinical worsening) should include evaluation of both CNS and 
systemic disease.
  
 
The eligibility criteria regarding patients with brain metastases should describe the eligibility for 
each of the following types of metastases:  
 
  Treated/stable metastases -- where patients have received prior CNS-directed therapy 
for their brain metastases and their CNS disease is stable, 
 
  Active metastases -- where patients have new brain metastases or progressive brain 
metastases that have not been subjected to CNS-directed therapy since documented 
progression, and 
 
  Leptomeningeal metastases -- where patients have metastases in the leptomeningeal 
space. Leptomeningeal disease (LMD) is a clinical diagnosis that is defined as positive 
  3  Contains Nonbinding Recommendations 
 
cerebrospinal fluid (CSF) cytology or unequivocal radiologic or clinical evidence of 
leptomeningeal involvement. 
 
A.  Recommendations for inclusion of patients with treated/stable brain 
metastases 
 
  Patients with treated/stable brain metastases should be included in trials unless 
there is a strong rationale to exclude such patients. 
 
  Inclusion of patients with treated/stable brain metastases should not be 
dependent on whether the drugs pharmacological properties predict 
penetration of the blood-brain barrier. 
 
  Patients should be neurologically stable prior to study entry to mitigate the 
uncertainty of attributing CNS toxicity to the investigational drug or 
underlying disease. To achieve this, consider limiting enrollment to patients 
receiving a stable or decreasing corticosteroid dose at the time of study entry. 
 
B.  Recommendations for inclusion of patients with active brain metastases 
 
  Patients with active brain metastases should not be automatically excluded 
from trials and should be included if the treating physician determines that 
immediate CNS specific treatment is unlikely to be required and:  
-  there is a strong rationale for likelihood of CNS activity, or 
-  CNS metastases are common in the target population. 
 
  For drugs with known CNS toxicities, exclusion of patients with active brain 
metastases may be justified, especially early in drug development.  
 
C.  Recommendations for inclusion of patients with leptomeningeal metastases 
 
  Patients with LMD should not be automatically excluded from trials and 
should be included if: 
-  the treating physician determines that immediate CNS specific 
treatment is unlikely to be required,  
-  the drug is anticipated to have CNS activity and is relevant for the 
primary tumor, and 
-  there is strong scientific rationale to support the likelihood of benefit, 
based on pre-existing data.  
 
D.  Recommendations for exclusion of patients with brain metastases 
 
  In early clinical development, for drugs with the potential to increase the risk 
of bleeding, patients with clinically symptomatic hemorrhage on brain 
imaging or receiving therapeutic anticoagulation should be excluded until 
  4  Contains Nonbinding Recommendations 
 
preliminary evidence of safety is available demonstrating that participants 
would not be exposed to unreasonable risk. 
 
  For drugs with the potential to lower seizure threshold, patients with a history 
of seizures should be carefully screened to assess the potential benefits and 
risks and optimization of their antiepileptic drug regimen. Exclusion of these 
patients until preliminary evidence of safety is available demonstrating that 
participants would not be exposed to unreasonable risk may be prudent. 
 
  For drugs with potential cytochrome P450 (CYP) interactions, patients on 
certain CYP inducing antiepileptic drugs should be considered for exclusion 
until preliminary evidence of safety is available demonstrating that 
participants would not be exposed to unreasonable risk. 
 
  For drugs whose efficacy may be compromised by concurrent corticosteroids, 
patients requiring corticosteroid use that exceeds a prespecified threshold 
should be considered for exclusion. 
 
E.  Baseline CNS screening  
 
One reason providers have been reluctant to perform screening CNS imaging is because 
detection of an asymptomatic lesion may preclude patient eligibility for a clinical trial. 
Expanding eligibility to include patients with brain metastases enables baseline imaging to be 
performed that does not result in automatic exclusion of all patients with brain metastases. 
Baseline CNS imaging is recommended to determine if eligibility criteria are met:  
 
  in patients with a known history of brain metastases,  
 
  in populations where the risk of brain metastasis is high, 
 
  if there are specific concerns related to inclusion of patients with brain metastases, and 
 
  if an objective of the study is to evaluate the effect of the investigational drug on CNS-
related efficacy outcomes. 
  5