Evaluating Cancer 
Drugs in Patients with 
Central Nervous 
System Metastases  
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) 
 
 
July 2021 
Clinical/Medical 
   
Evaluating Cancer 
Drugs in Patients with 
Central Nervous 
System Metastases  
Guidance for Industry 
 
Additional copies are available from: 
 
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Center for Drug Evaluation and Research 
Food and Drug Administration 
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and/or 
 
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 Food and Drug Administration 
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Email: ocod@fda.hhs.gov 
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) 
 
July 2021 
Clinical/Medical
  Contains Nonbinding Recommendations 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 1 
III.  CLINICAL TRIAL DESIGN CONSIDERATIONS ..................................................... 2 
A.  Patient Population .......................................................................................................................... 2 
B.  Available Therapy .......................................................................................................................... 2 
C.  Prior Therapies .............................................................................................................................. 3 
D.  Assessment of CNS Metastases ..................................................................................................... 3 
E.  Study Endpoints ............................................................................................................................. 4 
F.  Leptomeningeal Disease (LMD) ................................................................................................... 5 
  Contains Nonbinding Recommendations 
Evaluating Cancer Drugs in Patients with Central Nervous System 
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  
 
The purpose of this guidance is to describe FDAs recommendations for clinical trial designs of 
cancer drugs or biological products2 regulated by CDER and CBER that are intended to support 
product labeling describing the antitumor activity in patients with central nervous system (CNS) 
metastases from solid tumors originating outside the CNS.     
 
FDAs current thinking regarding inclusion of patients with brain metastases in clinical trials is 
addressed in the guidance for industry Cancer Clinical Trial Eligibility Criteria: Brain 
Metastases (July 2020).3 
 
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 FDA 
guidance means that something is suggested or recommended, but not required..  
 
II.  BACKGROUND 
 
The solid tumors that most often metastasize to the CNS are small cell and non-small cell lung 
cancers, breast cancer, melanoma, and renal cancers.4 CNS metastatic disease includes 
parenchymal metastases to the brain or spinal cord, as well as leptomeningeal disease (LMD) 
involving the pia, subarachnoid leptomeninges, and cerebrospinal fluid (CSF). LMD may present 
 
1 This guidance has been prepared by the Oncology Center of Excellence (OCE), the Center for Drug Evaluation and 
Research (CDER), and the Center for Biologics Evaluation and Research (CBER) at the Food and Drug 
Administration.  
2 For purposes of this guidance, references to drugs include drugs approved under section 505 of the FD&C 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 We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 
4 Nayak L, Lee EQ, Wen PY, 2012, Epidemiology of Brain Metastases, Curr Oncol Rep, 14(1): 48-54. 
  1  Contains Nonbinding Recommendations 
with or without concurrent parenchymal disease and represents widespread dissemination of 
cancer cells throughout the CNS. 
 
Metastatic cancer is a systemic disease; therefore, evaluation of the effectiveness of cancer drugs 
includes consideration of whether the cancer is controlled at all disease sites. The potential for 
benefit of a drug as assessed by tumor shrinkage of CNS lesions is uninterpretable without 
information regarding tumor shrinkage at extra-CNS disease sites. Furthermore, evaluation of 
anti-tumor activity, particularly durability of tumor response in the CNS may not be attributable 
solely to the investigational drug, as treatment would generally be changed at the time of extra-
CNS disease progression in patients with evidence of stable or responding CNS lesions. The 
recommendations below reflect the challenges in assessing the potential benefit of systemic 
therapies at a single disease site in patients with disease in, or at risk for disease progression in, 
CNS and extra-CNS sites.  
 
III.  CLINICAL TRIAL DESIGN CONSIDERATIONS 
 
The recommendations discussed below pertain to clinical trials for systemic anticancer drugs 
where patients with CNS metastases are included in the study population and CNS anti-tumor 
activity is intended to be described in product labeling. These recommendations are also 
applicable to trials conducted exclusively in patients with CNS metastases.  
 
A.  Patient Population 
 
FDA recognizes that treatment of CNS metastases presents several challenges and unique 
considerations (e.g., circumventing the blood-brain barrier); however, CNS disease should not be 
evaluated in isolation from metastatic disease in the rest of the body. FDA will evaluate effects 
of systemic drugs on CNS metastases in the context of the entire burden of metastatic disease, 
regardless of whether the trial was conducted exclusively in patients with CNS metastases or in a 
population where only a subset of patients has CNS metastases. Therefore, efficacy claims based 
on endpoints measuring CNS activity alone may not be appropriate. For example, evaluation of 
the clinical significance of overall response rates (ORR) or progression-free survival (PFS) that 
considers only CNS disease sites (CNS-ORR or CNS-PFS, respectively) is difficult to interpret 
as it does not take into account extra-CNS metastatic disease. Likewise, a labeling indication 
specifically for treatment of CNS metastases alone may not be appropriate. Where anti-tumor 
activity has been demonstrated in both the CNS and extra-CNS sites of disease, treatment effects 
on CNS metastases may be described in Section 14 (Clinical Studies) of the product label.   
 
B.  Available Therapy 
 
For the purposes of determining whether an expedited program is an appropriate regulatory 
pathway for a given drug, an available therapy for a metastatic solid tumor would be an available 
therapy5 for CNS metastases of that solid tumor, unless otherwise specified in the labeling for 
that therapy (e.g., the drug is contraindicated for CNS metastases). For example, since alectinib 
is approved for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive 
 
5 For the definition of available therapy, see section III.B of the guidance for industry Expedited Programs for 
Serious Conditions  Drugs and Biologics (May 2014). 
  2  Contains Nonbinding Recommendations 
metastatic non-small cell lung cancer (NSCLC), alectinib is considered available therapy for the 
treatment of patients with CNS metastases from ALK-positive NSCLC. Showing comparability 
to available therapy for treatment of overall metastases and demonstrating superiority for 
treatment of CNS metastases activity may be sufficient for expedited review consideration of a 
given drug. 
 
C.  Prior Therapies 
 
FDA recommends that trial designs incorporate the following elements regarding therapies that 
subjects may have received prior to enrolling in the trial: 
 
  Case report forms should be designed to capture information on all prior CNS-directed 
treatments such as surgery, stereotactic radiosurgery (SRS), or whole brain radiation 
therapy (WBRT), including the dates of such therapy and response to therapy at baseline. 
 
  The protocol should specify the interval between completion of CNS radiation therapy 
(RT) and study entry as an eligibility criterion. The interval should be of sufficient 
duration to allow attribution of treatment effects to the study intervention, and to reduce 
the likelihood of enrolling patients with radiographic post-RT pseudoprogression. In most 
cases, an interval of at least 12 weeks is recommended and a shorter interval may be 
acceptable when there is reasonable certainty of disease progression supported by 
additional information (e.g., histologically proven, new CNS lesion outside the RT field) 
prior to that time.  
 
  The protocol should specify at least one appropriate stratification factor for 
randomization to minimize bias based on prior therapy(ies) (e.g., treated vs. untreated 
CNS metastases at baseline; presence or absence of CNS metastases at baseline). 
 
D.  Assessment of CNS Metastases 
 
  Magnetic resonance imaging (MRI) with gadolinium contrast is the preferred imaging 
modality for tumor assessment.6 
 
  The protocol should require baseline imaging evaluation of the CNS in all enrolled 
patients to identify patients with CNS disease prior to initiation of protocol-specified 
therapy.  
 
  The protocol should apply accepted standard response criteria for evaluation of CNS 
disease (e.g., modified version of RECIST 1.1, Response Assessment in Neuro-Oncology 
 Brain Metastases [RANO-BM]). Any proposed modifications or adaptations to 
standard response criteria should be adequately justified.  
 
 
6 Lin NU, Lee EQ, Aoyama H, et al., 2015, Response assessment criteria for brain metastases: proposal from the 
RANO group, Lancet Oncology, 16(6): e270e278. 
  3  Contains Nonbinding Recommendations 
  The protocol should require on-study imaging assessments for CNS disease at the same 
time points as those for extra-CNS disease. Any unscheduled disease assessments (e.g., 
due to clinical worsening) should include evaluation of both CNS and extra-CNS disease. 
 
  Sponsors should provide a radiology charter describing the imaging modalities, 
sequences, and other standardized parameters that should be applied at all trial sites. 
 
  The protocol and the radiology charter should specify the conditions under which 
previously radiated lesions may be included as target lesions (e.g., documentation of 
progressive disease). 
 
  Case report forms should capture data at baseline and during the study on variables that 
may impact interpretation of radiographic response, including presence or change in 
neurological symptoms, concurrent steroid use/change in steroid use, and concurrent anti-
seizure medications/change in anti-seizure medications. 
 
E.  Study Endpoints 
 
The selection of the appropriate endpoint to evaluate CNS activity of a systemic drug will 
depend in part on the study population, including whether the trial is intended to evaluate only 
patients with CNS metastases.7 The following study endpoints may be considered: 
 
  Time-to-event endpoints 
 
  As discussed in the guidance for industry Clinical Trial Endpoints for the Approval of 
o
Cancer Drugs and Biologics, data derived from externally controlled trials are 
seldom reliable for time-to-event endpoints and those endpoints should therefore be 
evaluated in randomized, internally controlled trials. 
 
  Overall Survival (OS): 
 
  OS can generally only be evaluated in randomized controlled trials.  
o
 
  As it is challenging to accurately attribute death to CNS disease, death due to any 
o
cause should be used to determine OS. 
 
  Endpoints based on tumor assessment: 
 
  Key efficacy endpoints based on tumor assessments should incorporate evaluation of 
o
both CNS and extra-CNS disease (see III.A). Specifically, the ORR and PFS should 
be determined based on evaluation of all metastatic disease, regardless of whether it 
occurs in the CNS or extra-CNS. 
 
 
7 See the guidance for industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics (December 
2018).   
  4  Contains Nonbinding Recommendations 
  When the primary endpoint is based on tumor assessment, it should be verified by 
o
independent, blinded central review with neuro-radiology expertise. Where necessary 
and when supported by adequate justification, a random sample-based blinded central 
review auditing approach could be used; such an approach should include a pre-
specified auditing plan with a strategy to detect potential assessment bias.  
 
  Capture CNS duration of response (DoR) in addition to systemic DoR. The 
o
proportion of patients with durable responses at specific time points (e.g., 6-month, 
12-month DoR) may also be described. 
 
  CNS overall response rate (CNS-ORR) may be uninterpretable in a population with 
o
recent CNS-directed therapy such as RT; therefore, responses should be reported 
based on time from prior RT (e.g., < 3 months, < 6 months). 
 
  Time to CNS progression or CNS-PFS may be uninterpretable due to censoring of 
o
patients at the time of extra-CNS progression or death, resulting in a large number of 
censored patients or disproportionate censoring. For solid tumors where the CNS is a 
common metastatic site, PFS in patients with brain metastases, the incidence of CNS 
as first site of progression, alone or with concurrent extra-CNS progression, may be 
reported.  
 
F.  Leptomeningeal Disease (LMD) 
 
  For the purposes of this guidance, FDA considers LMD to be a disease of the entire CNS 
compartment. Clinical trials intended to evaluate drug effects on LMD should also 
evaluate CNS parenchymal disease and efficacy claims will be based on assessment of 
disease in the entire CNS unless there is a biological rationale for why a product may 
affect LMD preferentially (e.g., local delivery to the CSF).  
 
  LMD can be identified based on imaging or CSF analysis; however, clinical symptoms 
should also be evaluated and followed. The presence of at least one site of MRI evaluable 
disease amendable to repeat assessment is preferred to establish and evaluate LMD.  
 
  Patients with suspected LMD by clinical symptoms only (without imaging findings), 
o
should undergo CSF analysis to substantiate the diagnosis of LMD.  
 
  Responses should be confirmed by follow-up imaging or cytology depending on how 
o
the diagnosis was established. 
  5