Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical Trials

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Considerations for the
Inclusion of Adolescent
Patients in Adult Oncology
Clinical Trials
Guidance for Industry
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Oncology Center of Excellence (OCE)
March 2019
Clinical/Medical

Considerations for the
Inclusion of Adolescent
Patients in Adult Oncology
Clinical Trials
Guidance for Industry
Additional copies are available from:
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Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
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https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
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Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Oncology Center of Excellence (OCE)
March 2019
Clinical/Medical

TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
III. 	CRITERIA FOR INCLUDING ADOLESCENT PATIENTS IN ADULT
ONCOLOGY CLINICAL TRIALS ................................................................................ 2
IV. 	DOSE SELECTION FOR ADOLESCENT PATIENTS IN ADULT ONCOLOGY
CLINICAL TRIALS......................................................................................................... 3
V. 	SAFETY MONITORING ................................................................................................ 4
VI. 	ETHICAL CONSIDERATIONS ..................................................................................... 4

Contains Nonbinding Recommendations
1
Considerations for the Inclusion of Adolescent
Patients in Adult Oncology Clinical Trials
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
The purpose of this guidance is to provide the pharmaceutical industry, clinical investigators, and
institutional review boards with information to facilitate the inclusion of adolescent patients (for
purposes of this guidance, defined as ages 12 to 17) in relevant adult oncology clinical trials.
FDA recommends the inclusion of adolescent patients in disease- and target-appropriate adult
oncology clinical trials to enable earlier access to investigational and approved drugs2 for
adolescent patients with cancer. Topics that are discussed in this guidance include the following:
• 	Appropriate criteria for the inclusion of adolescent patients in adult oncology clinical
trials at various stages of drug development
• 	Dosing and pharmacokinetic and pharmacodynamic evaluations
• 	Safety monitoring
• 	Ethical considerations
The information in this guidance is meant to serve as a general guideline for sponsors
considering this approach. Because specific details of an adult oncology drug development
program that includes adolescent patients will vary depending on the characteristics and
development stage of the drug and disease(s) under evaluation, sponsors are encouraged to
1 This guidance has been prepared by the Divisions of Hematology and Oncology Products and Clinical
Pharmacology V in the Center for Drug Evaluation and Research and the Oncology Center of Excellence (OCE) in
cooperation with the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration.
2 For purposes of this guidance, references to drugs includes drugs and biological products 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) that are drugs.

Contains Nonbinding Recommendations
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contact the responsible FDA review division to discuss details of the program before
implementation.
In addition, enrolling adolescent patients in adult oncology clinical trials may contribute toward
addressing pediatric regulatory requirements under section 505A or 505B of the Federal Food,
Drug, and Cosmetic Act. Details of these requirements should be discussed with the responsible
FDA review division.
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s 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
Cancers in young pediatric patients are often different from those in adult patients and require
unique treatment approaches; however, some cancers found in adolescent patients—such as
some soft tissue and bone sarcomas, central nervous system tumors, leukemias and lymphomas,
and melanoma—are similar in histology and biologic behavior to those found in adults.
Adolescent patients, because of their age, have historically been ineligible for enrollment in adult
oncology clinical trials, and the initial pediatric trials for many drugs are conducted years later,
often after the drug is approved in adults. As a result, adolescent patients may have delayed
access to potentially effective therapies. In addition, accrual of adolescent patients to pediatric
trials evaluating approved drugs may be difficult because patients can receive the drug through
off-label use.
III. 	CRITERIA FOR INCLUDING ADOLESCENT PATIENTS IN ADULT
ONCOLOGY CLINICAL TRIALS
Adolescent patients should be eligible for enrollment in adult oncology clinical trials at all stages
of drug development when the histology and biologic behavior of the cancer under investigation
is the same in, or the molecular target of the drug is relevant to, cancers in both adult and
adolescent patients.
The following are recommendations regarding including adolescent patients by stage of drug
development:
• 	First-in-human or dose-escalation trials:
‒ 	Adolescent patients may be enrolled after some initial adult pharmacokinetic and
toxicity data are obtained. The sponsor should consult with the responsible FDA
review division to determine the amount and type of adult data needed before
enrolling adolescent patients.

Contains Nonbinding Recommendations
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‒ 	In general, adolescent patients enrolled in these early phase trials should have cancers
that are relapsed after or refractory to standard therapy with no curative options or for
which no standard therapies with curative intent exist.
• 	Activity-estimating or confirmatory trials:
‒ 	Adolescent patients can be enrolled simultaneously with adults
IV. 	DOSE SELECTION FOR ADOLESCENT PATIENTS IN ADULT ONCOLOGY
CLINICAL TRIALS
Systemic exposure and clearance of drugs are generally similar in adolescent and adult patients
after accounting for the effect of body size on pharmacokinetics. Selection of an appropriate
dose for adolescent patients in clinical trials should be based on pharmacokinetic and/or
pharmacodynamic characteristics of the investigational drug with consideration of body size
effect on drug exposure, toxicity, and activity data (if available); the therapeutic index of the
drug; and dose- and exposure-response relationships in adults.3
The following are recommendations for dosing based on how the drug is dosed in adults:
• 	For drugs with body size-adjusted dosing for adults, adolescent patients should receive
the same body size-adjusted dose (mg/kg or mg/m2 ) that is administered in adults.
• 	For drugs administered as a fixed dose based on data showing no clinically meaningful
body size effect on drug exposure and toxicity in adults, a minimum body weight
threshold should be defined to prevent adolescent patients who have a lower body weight
than average from exceeding adult exposures.
‒ 	An FDA analysis of adult population pharmacokinetics of oncology drugs suggested
that 40 kg (the approximate median body weight of a 12-year-old4) is generally the
lower end of the body weight range that has no clinically relevant effect on drug
pharmacokinetics or safety. (This cutoff may change based on the characteristics of
the drug, including the effect of body size on pharmacokinetics, the therapeutic index,
and dose- and exposure-response relationships.)
‒ 	In general, adolescent patients who weigh at least 40 kg can receive the same fixed
dose administered in adults.
3 Selection of an appropriate dose for adolescent patients may be more complex for certain biological products that
are regulated by CBER. Sponsors of such products should consult with the relevant review division in CBER to
determine if there are specific considerations they should take into account with respect to their products.
4 See the Clinical Growth Charts web page under National Center for Health Statistics at the Centers for Disease
Control and Prevention website (https://www.cdc.gov/growthcharts/clinical_charts.htm).

Contains Nonbinding Recommendations
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‒ 	In general, adolescent patients who weigh less than 40 kg should switch to a body
weight (mg/kg) or body surface area (mg/m2 ) adjusted dose. This adjusted dose
should be based on an adult reference body size (e.g., the average adult body weight
of 70 kg or median body weight or surface area of the adult patient population
determined from existing data).
• 	Pharmacokinetic and/or pharmacodynamic (if available) samples should be collected
from adolescent patients included in the adult oncology drug development program.
V. 	SAFETY MONITORING
Safety data collected during the trial should be examined for any age-related differences.
The evaluation of developmental toxicities (e.g., growth derangements, fertility issues) that
require a long duration of follow-up may not be possible in the context of early phase trials;
however, the sponsor should develop a plan for longitudinal evaluation of potential
developmental toxicities when it is feasible, particularly in trials enrolling patients in earlier lines
of therapy.
Adolescent patients enrolled in adult oncology clinical trials should have access to appropriate
care providers and facilities necessary to address the clinical management of potentially unique
toxicities in this patient population, which may require pediatric oncology expertise.
Juvenile animal studies are not routinely needed before the enrollment of adolescent patients in
adult oncology clinical trials, unless clinical and/or nonclinical data do not provide sufficient
information on toxicities.5
VI. 	ETHICAL CONSIDERATIONS
Under 21 CFR 50.50, institutional review boards reviewing adult oncology clinical trials that
allow for the enrollment of adolescent patients must ensure that the provisions of 21 CFR part
50, subpart D, Additional Safeguards for Children in Clinical Investigations, and, specifically, 21
CFR 50.52, Clinical investigations involving greater than minimal risk but presenting the
prospect of direct benefit to individual subjects, are satisfied before approving the studies.
Considerations should include disease and/or molecular target, available therapeutic options, and
dose level for first-in-human trials.
Enrollment of appropriately selected adolescent patients in relevant adult oncology clinical trials
with appropriate dose considerations and adequate safety monitoring is justified given the severe
and life-threatening nature of their disease.
5 Leighton, JK, Saber H, Reaman G, and Pazdur R, 2016, An FDA Oncology View of Juvenile Animal Studies in
Support of Initial Pediatric Trials for Anticancer Drugs, Regul Toxicol Pharmacol, Aug; 79:142–143.