Cancer Clinical Trial 
Eligibility Criteria:  
Minimum Age 
Considerations for 
Inclusion of Pediatric 
Patients 
 
Guidance for Industry and IRBs
 
 
 
 
 
 
 
 
 
 
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:  
Minimum Age 
Considerations for Inclusion 
of Pediatric Patients 
 
Guidance for Industry and IRBs 
 
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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.  Considerations for including pediatric patients in adult cancer clinical trials ........................ 3 
1. Ethical considerations ..................................................................................................................... 3 
2. Regulatory considerations ............................................................................................................... 3 
3. General considerations for all trial phases ..................................................................................... 4 
4. Early phase trial considerations ...................................................................................................... 5 
5. Late phase trial considerations ........................................................................................................ 7 
  Contains Nonbinding Recommendations 
Cancer Clinical Trial Eligibility Criteria:  
Minimum Age Considerations for Inclusion of Pediatric Patients  
Guidance for Industry and IRBs1 
 
 
 
 
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 pediatric patients (i.e., children and adolescents) when appropriate. This guidance is 
intended to assist stakeholders, including sponsors and institutional review boards (IRBs), 
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; with organ dysfunction or prior or concurrent malignancies; 
and with brain metastases. 
 
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  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. 
Early evaluation and development of potentially effective drugs, particularly targeted drugs, in 
pediatric patients may provide information on safe and effective use, therefore reducing risks 
associated with off label use, and accelerate the development of effective, innovative therapies 
for pediatric patients. 
 
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 
 
This guidance discusses minimum age eligibility criteria for pediatric patients in cancer clinical 
trials for oncology indications predominantly occurring in adults and addresses specific 
situations in which the inclusion of pediatric patients may be appropriate (based on disease 
biology and clinical course, molecular target of the investigational drug, and/or its molecular 
mechanism).  
 
Historically, pediatric patients have not been included in adult clinical trials, which generally 
specify 18 years as the minimum age of eligibility. Pediatric trials of the same drug generally 
have been initiated after the completion of one or more adult clinical trials, or after the initial 
approval in adults, delaying development of and access to potentially effective new cancer drugs 
for the pediatric population. In some cases, separate pediatric trials may have been operationally 
infeasible because the disease occurs so rarely in pediatric patients. Such delay in or absence of 
formal evaluation in a clinical trial results in product labeling that includes no pediatric-specific 
information about dose, safety, efficacy, and long-term effects to inform patients and providers 
on a drugs use in this population. Designing clinical trials that include pediatric patients as 
appropriate, and including information regarding such pediatric study 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. 
 
This guidance focuses on providing recommendations for eligibility criteria for pediatric 
populations including both children (for purposes of this guidance, ages two years to less than 
                                                 
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. 
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  Contains Nonbinding Recommendations 
twelve years) and adolescents (for purposes of this guidance, ages twelve years to seventeen 
years).  
 
 
III.  RECOMMENDATIONS 
 
Eligibility of a specific pediatric population for a cancer clinical trial should be considered when 
there is clinical evidence or a strong scientific rationale to suggest that pediatric patients with a 
specific cancer diagnosis, histologic subtype, or tumor associated with the same relevant 
molecular target may benefit and when there is compelling nonclinical and/or adequate clinical 
information to sufficiently justify patient risk. We recommend that applicants seek advice from 
FDA before submitting protocols that include provisions for enrolling pediatric patients, 
particularly those less than 12 years of age, for possible development of the investigational drug 
for pediatric patients.    
 
A.  Considerations for including pediatric patients in adult cancer clinical trials 
 
1.  Ethical considerations 
 
There are several important ethical considerations specific to including pediatric patients in 
clinical trials outlined in the FDA regulations addressing human subject protection at 21 CFR 
part 50, subpart D, Additional Safeguards for Children in Clinical Investigations. These 
safeguards restrict the allowable risk to which a pediatric patient may be exposed. In particular, 
interventions or procedures, including the use of an investigational drug, in an oncology trial 
should be restricted to situations in which there is the prospect of direct clinical benefit to the 
individual pediatric patient. These clinical investigations may involve children if: (1) the risk is 
justified by the anticipated benefit to the subject, (2) the anticipated benefit-risk profile is at least 
as favorable as that presented by available alternative treatments, and (3) adequate provisions are 
made for soliciting the assent of the children and permission of their parents or guardians.6   
 
Furthermore, under 21 CFR 56.111(c), in order to approve research in which some or all of the 
subjects are children, an IRB must determine that all research complies with 21 CFR part 50 
subpart D.7  
 
2.  Regulatory considerations 
 
Sponsors may be able to meet the requirements in sections 505A and 505B of the Federal Food,  
                                                 
6 See the specifics of these regulations under 21 CFR part 50, subpart D.  
7 Similar principles are outlined in the HHS human subject protection regulations at 45 CFR part 46, subpart D and 
45 CFR 46.111(b). 
 
  3 
  Contains Nonbinding Recommendations 
Drug, and Cosmetic Act (FD&C Act)8,9 by including pediatric patients in adult clinical trials as 
discussed in this guidance. Details about how to meet these requirements for a particular 
development program should be discussed with the responsible FDA review division. Preliminary 
efficacy information from pediatric patients in adult clinical trials may help inform the design of a 
dedicated pediatric clinical trial to support a pediatric indication when warranted based on the 
preliminary results.    
 
3.  General considerations for all trial phases 
 
Sponsors seeking to include pediatric patient populations should evaluate pediatric formulations 
taking into account the age, size, physiologic condition, and treatment needs of pediatric patients 
to be studied. Depending upon the mechanism of action of the drug and its potential for 
impacting development, growth, and causing late effects, prospective long-term follow-up of 
pediatric patients may be warranted. Additionally, monitoring for clinically important age-related 
differences in the safety profile of the drug should be conducted.
  
 
Protocols that enroll pediatric patients should include pediatric oncology expertise during trial 
design as well as adequate pediatric expertise in IRB review. Pediatric oncologists should be part 
of the care team for pediatric patients enrolled in adult oncology clinical trials. Pediatric patients 
should also be treated in facilities appropriate to address the unique care needs of the pediatric 
population.  
 
a.  Considerations for children 
 
Types of evidence that could support inclusion of patients from two years of age10 to under age 
twelve years (i.e., support an assessment that there is a prospect of direct clinical benefit for a 
pediatric patient) include: 
 
  Clinical studies: Natural history and preliminary adult studies that provide data 
indicating children are likely to exhibit similar responses to the investigational drug, 
assuming there are no concerns for the potential for severe growth and developmental 
toxicities. Natural history studies documenting similarities in disease presentation and 
outcome in children and adults and assessment of data, if available, from adult 
clinical programs may support decisions related to enrolling children.   
 
                                                 
8 By convention, sections 505A and 505B of the FD&C Act are referred to by the names of the legislation that 
created them, the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA), 
respectively. FDA will adopt this naming convention in this guidance. 
9 For more information, see the Food and Drug Administration, Status Report to Congress, July 2016, Best 
Pharmaceuticals for Children Act and Pediatric Research Equity Act, available at 
https://www.fda.gov/downloads/ScienceResearch/SpecialTopics/PediatricTherapeuticsResearch/UCM509815.pdf, 
accessed on June 23, 2020.  
10 Generally, because infants including neonates and young children < 2 years of age may be particularly vulnerable 
to expected and unanticipated toxicity due to developmental concerns and age-dependent maturation of metabolic 
enzyme systems and organ function, children < 2 years should not be included in adult cancer trials. In rare 
instances, infants beyond the neonatal period may be appropriate candidates for select new drugs. However, 
enrollment of children < 2 years of age is best reserved for exceptional cases (for example, for a rare disease with no 
established therapy) and only after consultation with the FDA. 
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  Contains Nonbinding Recommendations 
  Nonclinical studies: In vivo and in vitro nonclinical data (including in silico or 
mechanism-based in vitro evidence), particularly when conducted using pediatric 
tumor model systems may provide sufficient evidence that the response of a disease 
to an investigational drug in children would be the same or similar to that in adults 
and support inclusion of pediatric patients. Modeling and simulation should be used 
to understand potential differences in pharmacokinetics (PK) and pharmacodynamics 
(PD) as well as dose selection. 
 
  Non-clinical or early clinical experience in adults regarding toxicity and adverse 
effects that can be used to guide benefit-risk assessment for children. 
 
  Predictive and prognostic biomarkers when available to appropriately inform 
eligibility criteria and provide assurance that appropriate pediatric patients are 
enrolled. 
 
  Evidence from other drugs (approved or investigational) in the same pharmacological 
class or with similar mechanism of action. 
 
Presentation of more than one type of evidence increases the strength of the evidence for 
including children in adult clinical trials. 
 
b.  Considerations for adolescents 
 
As discussed in the guidance for industry Considerations for the Inclusion of Adolescent Patients 
in Adult Oncology Clinical Trials,11 sponsors should consider including adolescents (i.e., ages 
twelve years to seventeen years) in disease- and/or target-appropriate adult cancer clinical trials 
at all stages of development when appropriate conditions are met (see sections III.4.b and III.5).  
 
4.  Early phase trial considerations  
 
FDA encourages including pediatric patients for conditions with no curative options or for which 
no standard therapies with curative intent exist in early-phase trials that assess dose, safety, and 
PK when compelling nonclinical data and/or early adult clinical data suggest activity.  
 
Prospective planning to include pediatric patients in select first in human (FIH) studies intended 
for adults can be accomplished by designing studies to include an expansion cohort,12 which 
would begin enrollment of pediatric patients when adequate data on dose and safety in adults are 
available to assure that the clinical trial provides the prospect for direct clinical benefit to 
pediatric patients to justify the risks. In addition to evidence of activity, the study drug dosage 
and the duration of treatment should be expected to support a prospect of direct clinical benefit to 
                                                 
11 March 2019. 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. 
12 For more information, see the draft guidance for industry Expansion Cohorts: Use in First-in-Human Clinical 
Trials to Expedite Development of Oncology Drugs and Biologics (August 2018). When final, this guidance will 
represent the FDAs current thinking on this topic. 
 
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  Contains Nonbinding Recommendations 
children (21 CFR 50.52). The pediatric starting dose may be informed by clinical data, 
nonclinical data, and modeling and simulation, as appropriate. 
 
As discussed in the draft guidance for industry Expansion Cohorts: Use in First-in-Human 
Clinical Trials to Expedite Development of Oncology Drugs and Biologics,13 in exceptional 
circumstances, substantive nonclinical evidence of activity in tumor-derived cell lines or patient-
derived xenografts of pediatric tumors alone may provide sufficient justification for enrollment 
of a pediatric cohort before the availability of full clinical data in adults. In these situations, 
sponsors should consider staged enrollment of older children or adolescents before younger 
children, when justified by the toxicity profile of the investigational drug and possible 
developmental adverse effects. 
 
a.  Considerations for children 
 
In situations where there may be a concern regarding differential efficacy between adults and 
pediatric patients for the same or different indication,sponsors could consider enrolling an 
 
expanded population with patients under 12 years of age with the goal of including them in the 
safety analysis but not in the primary adult efficacy analysis.  
 
Potential ways to include pediatric patients after a sufficient number of adult patients have been 
evaluated to provide adequate safety and toxicity data include:  
 
  Enrolling a cohort of pediatric patients starting one dose level behind the highest dose 
level studied in adults in which there are no dose-limiting toxicities identified or one 
dose level below the maximally tolerated dose, if established. 
 
  The pediatric starting dose should be lower than the adult maximally tolerated dose 
(particularly for monoclonal antibodies) (i.e., the pediatric starting dose may be the 
adult recommended phase 2 dose (RP2D) if the dose is not the adult maximally 
tolerated dose).  
 
  A limited dose escalation may occur in the pediatric cohort depending on the 
therapeutic product and the clinical indication(s) as well as the specific age eligibility 
for the pediatric cohort.  
 
  In general, for children < 12 years of age defined adult flat doses would be converted 
to body surface area or body weight adjusted dosing. Dosing should be supported by 
the PK characteristics of the drug with consideration of the effect of body size on its 
PK, the therapeutic index of the drug, and dose- and exposure-response relationships, 
if known.   
 
  Enrolling pediatric patients in a separate cohort that will accrue concurrently with the 
adult cohort when sufficient information to permit dose modeling based on adult PK 
and exposure data are available. 
                                                 
13 When final, this guidance will represent the FDAs current thinking on this topic. 
  6 
  Contains Nonbinding Recommendations 
 
Possible strategies for the evaluation of efficacy in the pediatric population or indication(s) 
include: 
 
  Enroll pediatric patients in separate expansion cohorts prespecified to separately 
evaluate efficacy if the biology/clinical course of the disease differs in adults and 
children. 
 
  Use an expanded cohort design to build knowledge including assessment of safety 
and efficacy in particular populations. This approach would be particularly useful 
when the adult and pediatric indications ultimately under evaluation differ and in the 
setting of histology/tissue agnostic development strategies. 
 
b.  Considerations for adolescents 
 
Given similarities in drug exposure between adolescents and adults (based on similar body 
weight and metabolic processes), adolescents may be enrolled concurrently with adult patients 
after some initial adult PK and toxicity data are obtained.14   
 
5.  Late phase trial considerations 
 
The minimum age of eligibility specified in late-phase trials should be tailored to the biology of 
the disease under study, the scientific objectives of the trial, and the existing data regarding the 
mechanism of action, safety profile, and preliminary efficacy information. 
                                                 
14 For more information, see the guidance for industry Considerations for the Inclusion of Adolescent Patients in 
Adult Oncology Clinical Trials. 
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