FDARA Implementation Guidance for Pediatric Studies of Molecularly Targeted Oncology Drugs: Amendments to Sec. 505B of the FD&C Act: Guidance for Industry

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

FDARA
Implementation
Guidance for Pediatric
Studies of Molecularly
Targeted Oncology
Drugs: Amendments to
Sec. 505B of the FD&C
Act
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)
May 2021
Procedural

FDARA Implementation
Guidance for Pediatric
Studies of Molecularly
Targeted Oncology Drugs:
Amendments to Sec. 505B of
the FD&C Act
Guidance for Industry
Additional copies are available from:
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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)
May 2021
Procedural

Contains Nonbinding Recommendations
TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
III. 	REGULATORY CONSIDERATIONS .......................................................................... 4
A. 	Molecular Target ........................................................................................................................... 4
B. 	Considerations in the Determination of Relevance ..................................................................... 5
C. 	Target Lists ..................................................................................................................................... 6
1. The Relevant Molecular Target List ................................................................................................ 7
2. The Non-Relevant Molecular Target Leading to Waiver List.......................................................... 7
D. 	Content of the Initial Pediatric Study Plan and Description of Recommended Study(ies) ..... 8
1. iPSP content ..................................................................................................................................... 8
2. Description of recommended study or studies to be included.......................................................... 9
3. Early advice on pediatric development meetings for oncology projects subject to the amended
provisions of section 505B of the FD&C Act................................................................................. 11
E. 	Oncology Drug Combination Regimens .................................................................................... 11
F. 	Additional Consideration for Rare Cancers.............................................................................. 12
1. Pediatric cohorts in existing adult trials ....................................................................................... 12
2. Embedded pediatric trials .............................................................................................................. 12
3. Adolescent patients ........................................................................................................................ 12
4. Tissue/histology agnostic development .......................................................................................... 13
5. Master protocols ............................................................................................................................ 13
6. Model informed drug development (MIDD) .................................................................................. 13
G. 	Basis for Planned Waivers and Deferrals .................................................................................. 13
1. Waivers .......................................................................................................................................... 14
2. Deferrals ........................................................................................................................................ 14
IV. 	GLOBAL IMPLICATIONS AND INTERNATIONAL COLLABORATION ........ 15
A. 	Pediatric Cluster Teleconferences .............................................................................................. 15
B. 	Common Commentary Process .................................................................................................. 16
C. 	Formal Parallel Scientific Advice (PSA) .................................................................................... 16

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FDARA Implementation Guidance for Pediatric Studies of Molecularly
Targeted Oncology Drugs: Amendments to Sec. 505B of the FD&C Act
Guidance for Industry 1
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
This guidance addresses early planning for pediatric evaluation of certain molecularly targeted
oncology drugs 2 for which original New Drug Applications (NDAs) and Biologics License
Applications (BLAs) 3 are expected to be submitted to the FDA, in accordance with section 505B
of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (also referred to as the Pediatric
Research Equity Act, or PREA) as amended by the FDA Reauthorization Act of 2017
(FDARA). 4 Early pediatric evaluation of certain molecularly targeted oncology drugs as
required by section 505B(a)(1)(B) of the FD&C Act is expected to accelerate the creation of a
pediatric development plan and ultimately the development of promising drugs for pediatric
patients.
This guidance addresses the implementation of amendments made by FDARA section 504 to
section 505B of the FD&C Act regarding molecularly targeted oncology drugs. This guidance
does not address in detail the general requirements for development of drugs for pediatric use
under PREA or section 505A of the FD&C Act (also referred to as the Best Pharmaceuticals for
Children Act, or BPCA).
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,
1 This guidance has been prepared by the Oncology Center of Excellence in cooperation with the Center for Drug
Evaluation and Research and the Center for Biologics Evaluation and Research at the Food and Drug
Administration.
2 For purposes of this guidance, references to drugs and drug products include drugs approved
under section 505 of the Federal Food, Drug, and Cosmetic Act (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 For additional information about PREA requirements and proposed biosimilar products, see Q.I.16. in the draft
guidance for industry New and Revised Draft Q&As on Biosimilar Development and the BPCI Act (Revision 2)
(December 2018) (when final, this guidance will represent FDA’s current thinking on this topic).
4 Public Law 115-52, 131 Stat. 1005 (August 18, 2017).

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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
Section 504 of FDARA amended section 505B of the FD&C Act to require—for original
applications submitted on or after August 18, 2020—pediatric investigations of certain targeted
cancer drugs with new active ingredients, based on molecular mechanism of action rather than
clinical indication. Specifically, if an original NDA or BLA is for a new active ingredient, and
the drug that is the subject of the application is intended for treatment of an adult cancer and
directed at a molecular target FDA determines to be substantially relevant to the growth or
progression of a pediatric cancer, reports on the molecularly targeted pediatric cancer
investigation required under section 505B(a)(3) of the FD&C Act must be submitted with the
marketing application, unless FDA waives or defers the requirement. 5 FDARA thus created a
mechanism to require evaluation of certain novel drugs that may have the potential to address an
unmet medical need in the pediatric population (specifically, pediatric cancer patients <17 years
of age). 6 Timely investigation in pediatric patients of the antitumor activity of potentially
effective targeted drugs under development in adults, and of those drugs’ toxicities relative to the
unique growth and developmental considerations of pediatric patients, is intended to accelerate
early pediatric evaluation of these products and ultimately facilitate development of appropriate
new therapies for pediatric patients.
Advances in the understanding of the molecular etiology and genetic epidemiology of human
cancer have transformed the paradigm of cancer drug development; molecularly targeted drugs
have advanced the concept of precision medicine in oncology. However, the extension of this
scientific development to pediatric cancers has been both delayed and limited due in part to the
fact that the requirements for pediatric assessments of new cancer drugs have historically been
based on indication (i.e., requirements for assessment of the safety and effectiveness of a drug
for intended or approved indications in relevant pediatric subpopulations). Generally, the types
of cancers in pediatric patients and adults differ in etiology, biology, organ of origin, and
natural history, which has sometimes resulted in pediatric trials not being required under the
pre-FDARA iteration of PREA (e.g., the requirements were waived because the drug in
question was being developed for a cancer that rarely or never occurs in children, thereby
making the necessary studies impossible or highly impracticable). In addition, new drugs
developed for rare cancers which do occur in both adults and pediatric patients are generally
exempt from PREA assessment requirements under section 505B(a)(1)(A) because they are for
indications for which orphan designation has been granted (see section 505B(k)(1) of the
FD&C Act).
5 Sections 505B(a)(1)(B) and 505B(a)(3)(C) of the FD&C Act. FDA anticipates that there may be additional
considerations for proposed biosimilar product applicants. For additional information about PREA requirements
and proposed biosimilar products, see Q.I.16. in the draft guidance for industry New and Revised Draft Q&As on
Biosimilar Development and the BPCI Act (Revision 2) (when final, this guidance will represent FDA’s current
thinking on this topic).
6 The amendments to 505B of the FD&C Act made by FDARA section 504 are sometimes referred to as The
Research Acceleration for Cure and Equity (RACE) for Children Act.

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However, malignancies occurring in children and adolescents can harbor the same molecular
abnormalities as those found in adult cancers despite differences in site of origin or histology,
and therefore, many new targeted oncology drugs may prove effective in the treatment of
pediatric patients with cancer, even if the adult cancer indication does not occur in the pediatric
population. Large scale pediatric cancer genome sequencing efforts, such as the National
Cancer Institute’s Therapeutically Applicable Research to Generate Effective Treatments
(TARGET) program 7 , the Pediatric Cancer Genome Project 8 , and the International Cancer
Genome Consortium’s PedBrain Tumor 9 and ICGC-MMML-seq 10 projects provide evidence
that the genetic and epigenetic repertoires of driver gene aberrations may differ between adult
and pediatric cancers. A growing body of evidence suggests that genetic and other molecular
biological vulnerabilities of certain adult cancers also exist in pediatric cancers. 11, 12 Up to 50%
of pediatric cancers have been reported to harbor a potentially druggable event, i.e., a molecular
abnormality which can be potentially addressed by a targeted drug already approved for use in
adults. 13
Section 505B of the FD&C Act, as amended by FDARA, requires that any original NDA or
BLA submitted on or after August 18, 2020, for a new active ingredient, must contain reports on
the molecularly targeted pediatric cancer investigation described in section 505B(a)(3) of the
FD&C Act, unless the requirement is waived or deferred, if the drug that is the subject of the
application is:
(1) intended for the treatment of an adult cancer, and
(2) directed at a molecular target that the Secretary determines to be substantially relevant
to the growth or progression of a pediatric cancer. 14
This requirement applies even if the adult cancer indication does not occur in the pediatric
population, and, per section 505B(k)(2) of the FD&C Act, even if the drug is for an adult
indication for which orphan designation has been granted.
A supplemental application will not trigger the requirement to submit reports on the molecularly
targeted pediatric cancer investigation described in section 505B(a)(3) of the FD&C Act (see
section 505B(a)(1)(B) of the FD&C Act).
7 For additional information, see https://ocg.cancer.gov/programs/target (accessed May 18, 2021).
8 For additional information, see https://www.stjude.org/research/pediatric-cancer-genome-project.html and
https://pecan.stjude.cloud/ (accessed May 18, 2021).
9 For additional information, see http://www.pedbraintumor.org/ (accessed May 18, 2021).
10 For additional information, see the ICGC data portal at https://dcc.icgc.org (accessed May 18, 2021).
11 Gröbner SN, Worst BC, Weischenfeldt J, et.al., 2018, The Landscape of Genomic Alterations Across Childhood
Cancers, Nature, 555:321-327.
12 Ma X, Liu Y, Liu Y, et. al., 2018, Pan-Cancer Genome and Transcriptome Analyses of 1,699 Paediatric
Leukaemias and Solid Tumours, Nature, 555:371-376.
13 See footnotes 11 and 12.
14 Section 505B(a)(1)(B) of the FD&C Act. FDA anticipates that there may be additional considerations for
proposed biosimilar product applicants. For additional information about PREA requirements and proposed
biosimilar products, see Q.I.16. in the draft guidance for industry New and Revised Draft Q&As on Biosimilar
Development and the BPCI Act (Revision 2) (when final, this guidance will represent FDA’s current thinking on this
topic).

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The statute directs FDA, in consultation with the National Cancer Institute (NCI), members of
the internal committee established under section 505C of the FD&C Act, and the Pediatric
Subcommittee of the Oncologic Drugs Advisory Committee (ODAC), to establish, publish,
and regularly update a list of molecular targets considered, on the basis of data the Agency
determines to be adequate, to be substantially relevant to the growth or progression of a
pediatric cancer, and that may trigger PREA requirements (see sections 505B(m)(1)(A) and
505B(m)(2) of the FD&C Act).
Molecular targets that are considered “not substantially relevant” to the growth or progression
of pediatric cancers, and that would warrant a waiver of molecularly targeted pediatric cancer
investigation requirements under PREA constitute a second list (see section 505B(m)(1)(B) of
the FD&C Act) (see section III.C for more information regarding the lists). FDA sometimes
refers to these as “The Relevant Molecular Target List” and “The Non-Relevant Molecular
Target Leading to Waiver List,” respectively. It is important to note, however, that the fact that
a drug is directed at a molecular target on the “relevant” list does not necessarily mean that
submission of reports on the molecularly targeted pediatric cancer investigation described in
section 505B(a)(3) of the FD&C Act is required. In some cases, for example, a waiver may be
warranted (see section 505B(a)(5) of the FD&C Act). Nor does the absence of the molecular
target on the Relevant Molecular Target List necessarily mean that submission of such reports
is not required under section 505B(a)(1)(B) of the FD&C Act; the requirement depends, in part,
on whether FDA has determined the molecular target to be substantially relevant to the growth
or progression of a pediatric cancer but does not depend on the presence of absence of the
molecular target on any list. Nevertheless, the lists are a guide to sponsors as they consider
development plans for new targeted drugs and early pediatric assessments in light of the
amended PREA provisions.
III. 	REGULATORY CONSIDERATIONS 15
A. 	Molecular Target
For purposes of section 505B of the FD&C Act, the Agency interprets a “molecular target” in
cancer drug development as a molecule in human cells (normal or cancer cells) that is
intrinsically associated with a particular malignant disease process such as etiology, progression,
and/or drug resistance. For a molecule to be considered a molecular target for purposes of
section 505B, there should be evidence that addressing (i.e., binding to, interacting with) the
molecule with a drug produces a measurable effect on a cancer in vivo or in vitro which may
translate clinically to a favorable objective change in the disease process. An example of what
FDA currently considers to be a molecular target for purposes of section 505B is the CD19
antigen on B cell precursor malignancies wherein exposure of antigen positive tumor cells to
15 While this guidance focuses on requirements related to molecular targets under PREA, FDA also intends to take
into account certain of the considerations described in this section of the guidance (e.g., considerations relating to
whether a molecular target is substantially relevant to the growth or progression of a pediatric cancer and those
relating to innovative study designs for rare cancers), as appropriate, to streamline and improve the Written Request
process under section 505A of the FD&C Act, including amendments to Written Requests.

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anti-CD19 antibodies, bi-specific antibodies, antibody-drug conjugates, or specifically
engineered cell products, results in tumor cell killing.
B. 	Considerations in the Determination of Relevance
FDA intends to consider all available evidence when determining whether a molecular target is
substantially relevant to the growth or progression of pediatric cancer. A specific or minimum
evidence standard for determining target relevance is not feasible because of the different classes
and characteristics of molecular targets, variability in the existing scientific evidence base among
targets, and continuously emerging science. FDA is responsible for determining whether a
molecular target is substantially relevant for purposes of section 505B of the FD&C Act.
Molecular targets that lack sufficient evidence for FDA to determine whether they are
“substantially relevant” or “not substantially relevant” will not be included in a target list;
however, the lists will be updated regularly 16 to reflect new information regarding the relevance
of molecular targets.
Although this list is not exhaustive, one or more of the following considerations may, as
appropriate, inform FDA’s determination that a molecular target is substantially relevant for
purposes of section 505B:
• 	Acceptable levels of evidence that the target has been shown to be associated with
one or more types of cancer which occur in pediatric patients. For targets within a
cancer cell lineage, the target is intrinsically or may be differentially expressed in the
cancer cells of interest compared to normal site-specific tissues.
• 	The biological function of the target may be functionally related to the etiology,
growth, and therapy resistance of a cancer that occurs in pediatric patients. For a
gene abnormality, modulation of the affected gene product or a critical downstream
pathway or correction/deletion of the affected gene defect may adversely affect
cancer cells.
• 	Non-clinical in vitro or in vivo evidence of the target in one or more human cancers,
especially those occurring in pediatric patients.
o 	In vitro activity: Target modulation shows in vitro selectivity for cancer cell lines
containing/expressing the molecular target compared to the sensitivity of cell lines
not containing/expressing the target
o 	In vivo activity: Target modulation shows in vivo activity manifested as
stabilization of tumor growth or regression in models of pediatric cancers with the
molecular target of interest or relevant adult cancer models
o 	In vitro or in vivo activity of drugs in combination: When single agents do not
result in target modulation, support for substantial relevance may be found in
acceptable levels of evidence for additive or synergistic activity when an agent
which effects target modulation is used as part of a biologically rational
combination in appropriate in vitro and/or in vivo model systems.
• 	Clinical activity in adults with specific cancers (including, where available, objective
responses and improvement in outcomes), for which direct evidence demonstrates
that target modulation by investigational drugs is known to affect tumor growth.
16 See section 505B(m)(1) of the FD&C Act.

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• 	Predictive biomarkers associated with responsive tumor types which occur in adults
and also expressed by cancers that occur in pediatric patients and predict response to
target modulation. These may also aid in selection of the appropriate pediatric study
population for assessment of a novel, targeted drug.
Data from non-clinical evaluations of a drug’s activity in adult tumors can contribute some
evidence for the substantial relevance of a target to the growth or progression of a pediatric
cancer. Additional evidence, when necessary, can be obtained from non-clinical studies using a
pediatric-specific model system. Therefore, efforts should be made to initiate pediatric non-
clinical investigations early in the development timeline of a new molecularly targeted drug. An
appropriate pediatric pre-clinical model should be used whenever such a relevant pediatric model
is available. These may include, but are not limited to, the following models derived from a
tumor or tumors that occur in children: cell lines; xenografts, including patient-derived
xenografts and orthotopic xenografts; and organoids. Sponsors are encouraged to collaborate
with academic and other investigators in pediatric pre-clinical testing consortia, such as the NCI-
supported pediatric pre-clinical testing program and related activities and groups.
FDA, with input from NCI, may determine that available evidence demonstrates that a molecular
target is not substantially relevant to the growth or progression of pediatric cancer based on, for
example, the absence of a biologic rationale for a specific target’s function as an oncogenic
driver, or a lineage associated target that is not a component of a pediatric cancer cell, or pre-
clinical data that demonstrates no tumor cell growth effect by inhibition of the target.
C. 	Target Lists
A variety of information sources have been examined by FDA and NCI in the development of
the Relevant Molecular Target List and the Non-Relevant Molecular Target Leading to Waiver
List. These information sources, which include those listed below, have been supplemented by
input from international subject matter experts, reviewed by members of the Pediatric
Subcommittee of the ODAC, and vetted during public meetings:
• 	TARGET database (https://ocg.cancer.gov/programs/target)
• 	St. Jude’s Pediatric Cancer Genome Project
(https://www.stjude.org/research/pediatric-cancer-genome-project.html)
• 	St. Jude’s PeCan data portal (https://pecan.stjude.cloud/)
• 	NCI MATCH Trial (https://www.cancer.gov/about-cancer/treatment/clinical-
trials/nci-supported/nci-match)
• 	INdividualized Therapy FOr Relapsed Malignancies in Childhood-INFORM
(https://www.dkfz.de/en/inform/)
• 	The International Cancer Genome Consortium’s (ICGC) PedBrain Tumor
(http://www.pedbraintumor.org/
• 	ClinicalTrials.gov (https://clinicaltrials.gov/)
• 	Literature search (e.g., PubMed, Embase, and Google scholar). Published data
supporting target relevance were considered most informative when independently
validated reports of associations between a target and tumor type(s) were found in
subsequent peer-reviewed publications. Single case reports of an association between
a target and a pediatric cancer without evidence of effect on tumor growth by

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interference with the target were considered less informative. Efforts to expand the
evidence base of currently published targets and identify additional targets using text-
mining algorithms to assess publications for evidence are ongoing in the Office of
Clinical Pharmacology Division of Applied Regulatory Science and the Oncology
Center of Excellence.
1. 	The Relevant Molecular Target List
The list includes molecular targets considered, on the basis of data the Agency determines to be
adequate, to be substantially relevant to the growth or progression of one or more pediatric
cancers (see section 505B(m)(1)(A) of the FD&C Act). Categories may include, for
example:
• 	Targets Related to Specific Gene Abnormalities
• 	Targets Associated with Cell Lineage Determinants
• 	Targets on Normal Immune Cells and Cellular Components of the Tumor
Microenvironment
• 	Other Targets Associated with Specific Pathways or Functional Mechanisms of
Normal and/or Malignant Cells.
2. 	The Non-Relevant Molecular Target Leading to Waiver List
The list includes molecular targets of new cancer drugs in development for which pediatric
cancer study requirements under PREA will be automatically waived (see section 505B(m)(1)(B)
of the FD&C Act). This includes targets for which there are adequate data to determine that the
targets are not substantially relevant to the growth or progression of one or more pediatric
cancers. FDA anticipates that it will agree with sponsors’ plans (as outlined in their initial
pediatric study plans (iPSPs)) to request full waivers for pediatric evaluation under section
505B(a)(1)(B) of the FD&C Act of oncology drugs with a molecular target that is on the Non-
Relevant Molecular Target Leading to Waiver List.
FDA plans to regularly update the lists based on information from, for example, public
workshops or meetings, including meetings of the Pediatric Subcommittee of the ODAC. In
addition, the Federal Register Notice [Docket No. FDA-2018-N-3633] published on October 17,
2018, announced the opening of a docket to allow public comment with respect to possible
additions to or deletions from the published lists. The Pediatric Subcommittee of the ODAC
reviews all such comments.
These lists are available at the following link: Molecular Target Lists
(https://www.fda.gov/about-fda/oncology-center-excellence/pediatric-oncology).

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D. 	Content of the Initial Pediatric Study Plan and Description of Recommended
Study(ies)
Section 505B(e) of the FD&C Act requires applicants subject to PREA to submit an iPSP prior
to the submission of an NDA or BLA. 17 Prior to the enactment of FDARA, which added
sections 505B(a)(1)(B) and 505B(a)(3) to the FD&C Act, the pediatric study plans for
oncology drugs were generally proposals to request waivers for pediatric studies because the
adult cancer indications for which a drug was developed often did not occur or occurred only
rarely in pediatric patients, making pediatric studies in those indications impossible or highly
impracticable. 18 An extensive list of cancer diagnoses occurring almost exclusively in adults
thus is included in a list of adult-related conditions that qualify for a waiver of assessments
required under section 505B(a)(1)(A) of the FD&C Act because they rarely or never occur in
pediatrics. 19 The provisions for PREA mandated studies for oncology drugs under section
505B(a)(1)(B), however, require that certain oncology drugs for adult cancer indications be
studied based on the molecular mechanism of action of the investigational drug rather than
clinical indication. Therefore, an original application for a new active ingredient that is
submitted on or after August 18, 2020, and for which the drug that is the subject of the
application is intended for the treatment of an adult cancer and is directed at a molecular target
determined to be substantially relevant to the growth or progression of a pediatric cancer, must
include reports on the molecularly targeted pediatric cancer investigation described in section
505B(a)(3) of the FD&C Act, unless the requirement is waived or deferred. 20 Applicants
subject to this requirement will be required to submit iPSPs outlining the planned pediatric
study or studies, in accordance with section 505B(e) of the FD&C Act. Sponsors are advised
of the opportunity to seek early interaction with FDA to address their pediatric development.
Questions can be addressed to the Pediatric Oncology Program in the FDA’s Oncology Center
of Excellence and sponsors may submit a request for an early advice meeting through the
appropriate review division or office (see section III.D.3).
1. 	iPSP content
Details of the required iPSP contents and format can be found in section 505B(e)(2)(B) of the
FD&C Act. Additionally, FDA has issued a guidance for industry, Pediatric Study Plans:
Content of and Process for Submitting Initial Pediatric Study Plans and Amended Initial
Pediatric Study Plans (the iPSP Guidance) (July 2020). The iPSP Guidance describes, among
other things, FDA’s recommendations regarding iPSP content. A suggested iPSP template is
included in an appendix of the iPSP Guidance. An iPSP for a molecularly targeted oncology
17 See sections 505B(a)(1)(A), 505B(a)(1)(B), and 505B(e)(1) of the FD&C Act.
18 See section 505B(a)(5) of the FD&C Act.
19 See the list of “Adult-Related Conditions that qualify for a waiver because they rarely or never occur in
pediatrics” at https://www.fda.gov/media/101440/download.
20 See section 505B(a)(1)(B) of the FD&C Act. FDA anticipates that there may be additional considerations for
proposed biosimilar product applicants. For additional information about PREA requirements and proposed
biosimilar products, see Q.I.16. in the draft guidance for industry New and Revised Draft Q&As on Biosimilar
Development and the BPCI Act (Revision 2) (when final, this guidance will represent FDA’s current thinking on this
topic).

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drug must include an outline of the planned pediatric study or studies 21 and should include the
following elements, where applicable:
• 	Description of the cancer(s) in the pediatric population for which the drug may or
may not warrant early evaluation based on the molecular mechanism of action of the
drug
• 	Overview of the drug product including mechanism of action and the molecular target
to which the drug is directed
• 	Overview of planned extrapolation, where appropriate, of effectiveness in adults to
the pediatric population
• 	Planned request for drug-specific waivers and partial waivers with justification
• 	Planned request for deferrals of pediatric studies
• 	Tabular summary of proposed non-clinical and clinical studies
• 	Age-appropriate formulation including details of existing/planned excipients
• 	Non-clinical studies, including, for example:
o 	Data from proof-of-concept studies (planned and completed) for the adult
development program, if relevant
o 	Data from proof-of-concept studies in pediatric tumor models to support clinical
studies in pediatric patients
• 	Adult clinical data and any pediatric clinical data, if available, to support the pediatric
study or studies
• 	Planned pediatric safety, dosing, and preliminary efficacy study(ies) and other studies
that the sponsor may plan to include as part of a broad or focused pediatric
development program
• 	Timeline of pediatric development plan
• 	Agreements for pediatric studies with other regulatory agencies
2. 	Description of recommended study or studies to be included
A study(ies) to be described in the iPSP under section 505B(e) of the FD&C Act should
evaluate dosing based on PK, allometric scaling of adult PK, or physiologically-based PK-
modeling; safety; and preliminary efficacy. The study(ies) should typically be a non-
hypothesis-testing, single-arm study(ies) using standard response assessments such as overall
response rate and duration of response at a minimum.
Objectives of the study or studies described in the iPSP under section 505B(e) of the FD&C
Act should include the following:
• 	Evaluating tolerability and identifying dose limiting toxicities in pediatric patients
• 	Evaluation of PK across various age groups as appropriate
• 	Definition of the pediatric Recommended Phase 2 Dose(s) (RP2D) and schedule
• 	Preliminary assessment of activity (defined as overall response rate (ORR) or other
agreed relevant endpoint) across the entire study population, in biomarker enriched
21 See section 505B(e)(2)(B) of the FD&C Act.

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population(s), in pre-specified disease cohorts, or in adaptive design settings, in
successively opened disease cohorts as evidence of activity warrants
Sample size may vary but should support the study objectives. Factors to consider should
include the frequency of the molecular target expected across pediatric cancers in general and/or
within a specified histology or sub-type, the number of dose levels to be evaluated to identify a
recommended pediatric dose, and statistical considerations including estimated response rate that
would support further development, recognizing that in some circumstances, the numbers of
patients included in studies may be too small to provide statistically significant differences.
More definitive evaluation of a product, if warranted based upon the initial pediatric
evaluation(s) described in the iPSP, may be the subject of a proposed pediatric study request
(PPSR). Following review of the PPSR, which may include the study(ies) described in the
agreed iPSP, and discussions with the sponsor, FDA may issue a Written Request, if
appropriate. 22 Although not a requirement, planning for and including in the iPSP an additional
study(ies), contingent upon the results of the required molecularly targeted pediatric cancer
investigation described in section 505B(a)(3) of the FD&C Act, may facilitate early discussions
between the sponsor and FDA regarding a comprehensive pediatric development plan, despite
the fact that the timelines for submission and review for iPSPs and PPSRs differ.
Requirements relating to the protection of human subjects in FDA-regulated clinical
investigations are set forth in 21 CFR parts 50 and 56; additional safeguards for children are
included in 21 CFR part 50, subpart D (Additional Safeguards for Children in Clinical
Investigations). Institutional review boards (IRBs) are required to review clinical investigations
involving children as subjects covered by 21 CFR part 50, subpart D and approve only those
clinical investigations that satisfy the criteria and other conditions set forth in subpart D (see 21
CFR 50.50). Unless the risks of a molecularly targeted drug in a clinical investigation are no
more than a minor increase over minimal risk (see 21 CFR 50.53), the administration of a
molecularly targeted drug in children must offer the prospect of direct benefit to individual
subjects, the risk must be justified by the anticipated benefit to the subjects, and the anticipated
risk-benefit profile must be at least as favorable as that presented by available alternative
approaches (see 21 CFR 50.52). Additionally, adequate provisions must be made to obtain the
permission of the parents or guardians and, if appropriate, the assent of the children (see 21 CFR
50.52(c) and 50.55).
FDA recommends collaboration with recognized subject matter experts, including those
involved in clinical trial networks, academic investigators, and patient advocates early in the
development of the iPSP to develop an appropriate clinical rationale and scientifically rigorous
study design in clinically relevant diagnoses or subgroups of patients with the same diagnosis,
or groups defined by biomarker detection of the target of interest irrespective of specific
diagnosis. FDA anticipates that this will facilitate assessment of the feasibility of clinical
evaluations in the targeted patient population. If a diagnostic test (e.g., for a biomarker) is
utilized as part of a study, early discussion with FDA’s Center for Devices and Radiological
Health (CDRH) is encouraged regarding Investigational Device Exemptions and the use of
companion or complementary diagnostics.
22 For additional information regarding Written Requests, see section 505A of the FD&C Act (21 U.S.C. 355a).

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3. 	Early advice on pediatric development meetings for oncology projects subject to
the amended provisions of section 505B of the FD&C Act
Sponsors planning to submit applications may request a meeting 23 with the Oncology Center of
Excellence Pediatric Oncology Program, including, for example, pediatric oncologists from
review divisions in the Office of Oncologic Diseases in CDER or the Office of Tissue and
Advanced Therapies in CBER, and other disciplines (e.g., clinical pharmacology; statistics;
pharm tox; and chemistry, manufacturing, and controls (CMC), as appropriate). These meetings
are intended to provide an opportunity to discuss the Agency’s current thinking about the
relevance of a specific target and the expectations for early assessment in the pediatric
population unless justification for a waiver or deferral can be provided. The cover letter for
these meeting requests should clearly state “REQUEST FOR FDARA iPSP MEETING.” In
addition, sponsors should include a briefing document with the meeting request that includes all
relevant information, including the investigational drug’s mechanism of action and the molecular
target to which it is directed, the prevalence of the molecular target in one or more cancers that
predominate in the pediatric age group or the incidence in children of the rare cancer for which
the drug is being developed, known potential developmental toxicities from non-clinical studies,
extant adult efficacy and safety data, detailed chemical composition of the product’s active and
inactive ingredients, current formulation and plans for a pediatric appropriate formulation if
available, any anticipated unique toxicities for children, and the status of any regulatory filings
with other health authorities. Please contact the review division or office to schedule these
meetings and for any questions regarding these meetings. 24
E. 	Oncology Drug Combination Regimens
As discussed above, section 505B(a)(1)(B) of the FD&C Act applies to an original application
for a new active ingredient, if the drug that is the subject of the application is intended for the
treatment of an adult cancer and directed at a target that FDA determines to be substantially
relevant to the growth or progression of a pediatric cancer. Importantly, this requirement applies
to an original NDA or BLA for a new active ingredient for use in an oncology drug combination
regimen with a previously approved product, provided that the other criteria in section
505B(a)(1)(B) of the FD&C Act are satisfied. Thus, for such applications, an iPSP must be
submitted to the Agency containing an outline of the pediatric study or studies (of the new active
ingredient or the combination regimen, as appropriate) that the applicant plans to conduct and
any request for a deferral, partial waiver, or waiver, if applicable, along with any supporting
information (section 505B(e) of the FD&C Act).
23 See section 505B(e)(2)(C)(i)(I) of the FD&C Act, which describes early meetings on pediatric study plans for
drugs intended to treat a serious or life-threatening disease or condition.
24 Sponsors should consult the draft guidance for industry Formal Meetings Between the FDA and Sponsors or
Applicants of PDUFA Products (December 2017) or the draft guidance for industry Formal Meetings Between the
FDA and Sponsors or Applicants of BsUFA Products (June 2018), when finalized, to help ensure open lines of
dialogue before and during their drug development process. When final, these guidances will represent the FDA’s
current thinking on the topics therein.

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F. 	Additional Consideration for Rare Cancers
Given the challenges of stand-alone trials of investigational drugs in pediatric patients with a rare
cancer associated with a specific molecular target, FDA encourages innovation in study design,
which may, as appropriate, include Bayesian adaptive designs, the use of external controls
derived from patient-level data, the use of real world evidence, and the use of alternative
outcome measures such as patient reported outcomes (PROs) and pediatric PRO Common
Terminology Criteria for Adverse Events (CTCAE). FDA also encourages sponsors to request
feedback from FDA regarding plans for trial design and endpoints. Although not an exhaustive
list, the following scenarios may provide some options for maintaining the objective of early
pediatric assessment of drugs directed at substantially relevant targets and satisfy requirements of
section 505B of the FD&C Act in situations where a conventionally designed pediatric trial may
be inefficient or extremely difficult to conduct given the scarcity of affected pediatric patients.
1. 	Pediatric cohorts in existing adult trials
When a target being investigated in an adult clinical trial also occurs in a specific pediatric
tumor(s), sponsors may consider including a pediatric cohort during the initial or expansion
phase of a clinical trial. Including a pediatric cohort in an existing adult trial allows for the
inclusion of a specific pediatric population earlier in development of a targeted drug without
having to open an entirely new pediatric trial. This allows sponsors to use already existing
clinical sites and resources of the ongoing clinical trial, thus minimizing the resources and
infrastructure required to study the targeted drug in the pediatric population. 25, 26
2. 	Embedded pediatric trials
Embedding pediatric trials within an existing trial in adults may be particularly useful for the
evaluation of drugs with a molecular target that is rare in the pediatric population. Embedding a
pediatric trial within an adult trial could leverage resources of pre-existing global studies at
multiple sites, improving enrollment. The embedded study could also take advantage of existing
infrastructure arrangements (e.g., adding a sub-investigator rather than initiating a new study,
having consistent personnel) within study sites for adult patients.
3. 	Adolescent patients
When the molecular target of the drug is relevant to cancers in both adult and adolescent
patients, sponsors may consider including adolescent patients by lowering the age requirement
for enrollment. Systemic exposure and clearance of drugs are generally similar in adolescent and
adult patients after taking into account the effect of body size on pharmacokinetics. Inclusion of
adolescents in adult trials, when appropriate, would allow adolescent patients access to
investigational drugs with potential for benefit, and generate clinical trial data in this population
25 See 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 FDA’s
current thinking on this topic.
26 See guidance for industry and IRBs Cancer Clinical Trial Eligibility Criteria: Minimum Age Considerations for
Inclusion of Pediatric Patients (July 2020).

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that could be included in prescribing information for safe and effective use at the time of
approval. 27
In some instances, efficacy in adolescent patients may be extrapolated from adult data; however,
adequate approaches to evaluate safety in this population are required, regardless of whether
adolescents are included in adult studies or whether they are studied separately as part of the
broader pediatric population. 28
4. 	Tissue/histology agnostic development
Tissue agnostic studies may facilitate the development of targeted therapies in multiple pediatric
cancers with shared genetic aberrations (e.g., MSI-H/dMMR tumors, NTRK-fusion positive
tumors) or may incorporate pediatric cohorts in adult studies which share genetic aberrations
with pediatric cancers.
5. 	Master protocols
Master protocols, including basket and umbrella trials, may be appropriate mechanisms to assure
efficiency in light of the limited number of available patients for study and to minimize the
number of pediatric patients who may be exposed to ineffective therapies. Such master protocols
may involve pre-competitive discussions, negotiations, and planning by multiple sponsors. 29
FDA encourages sponsors and investigators to consider this approach given the large number of
similar- and same-in-class products to avoid unnecessary competition and duplication.
6. 	Model informed drug development (MIDD)
FDA encourages integration of MIDD approaches into pediatric cancer drug development as
appropriate. MIDD has been applied to predict clinical outcomes, inform clincial trial designs,
support evidence of effectiveness, optimize dosing, predict product safety, and evaluate potential
adverse events. MIDD approaches may provide a starting point for pediatric drug development
and, in some disease areas, inform dosing in pediatrics.
G. 	Basis for Planned Waivers and Deferrals
There may be circumstances, including those listed below, when a waiver or deferral may be
appropriate for a molecularly targeted pediatric cancer investigation. 30
27 See the guidance for industry Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical
Trials (March 2019).
28 See sections 505B(a)(2)(B) and 505B(a)(3)(B) of the FD&C Act.
29 See draft guidance for industry Master Protocols: Efficient Clinical Trial Design Strategies to Expedite
Development of Oncology Drugs and Biologics (September 2018). When final, this guidance will represent the
FDA’s current thinking on this topic.
30 See sections 505B(a)(3)(C), 505B(a)(4) and 505B(a)(5) of the FD&C Act.

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1. 	Waivers
FDA will grant a full or partial waiver, as appropriate, of the requirement to submit reports on
the investigation when the criteria set forth in section 505B(a)(5) of the FD&C Act are met.
Although decisions about each application will be made based on the facts of that application,
FDA anticipates that a full or partial waiver of such requirement may be appropriate in the
following circumstances (note that this is not an exhaustive list):
• 	If known (e.g., from studies conducted in adult humans or animals) or strongly
suspected (e.g., based on target biology) serious toxicity of a drug precludes its use in
all or one or more pediatric age groups.
• 	If there are known (e.g., from studies conducted in adult humans or animals) or
strongly suspected (e.g., based on target biology) severe developmental toxicities
which may present an unreasonable risk to pediatric patients of a particular
maturational stage.
• 	When a sponsor is not able to develop an appropriate pediatric formulation for an age
group.
• 	For studies of subsequently developed (i.e., later-generation) products with the
identical mechanism of action when ongoing, competing studies in the pediatric
population are being or have been conducted and when there is no convincing
evidence that the new active ingredient would provide a superior pharmacologic,
toxicity, or activity profile when compared to products with the same molecular
mechanism of action already studied or under investigation, potentially resulting in a
very small number of patients available to participate in a new investigation.
• 	When a drug or drugs with the same mechanism of action directed at the same
molecular target expressed in the same cancer(s) in children has/have failed to
demonstrate evidence of activity.
2. 	Deferrals
FDA may defer submission of reports on the investigation when the criteria set forth in section
505B(a)(4) of the FD&C Act are met. Although decisions about each application will be made
based on the facts of that application, a deferral of submission may be appropriate in the
following circumstances (note that this is not an exhaustive list): 31
• 	If the pediatric study(ies) should be delayed until additional safety or effectiveness
data have been collected; for example:
o 	until sufficient non-clinical evidence demonstrates tumor response to the known
inhibition of a defined molecular target(s) or pathway.
o 	when there is uncertainty regarding whether the activity of a drug occurs only in
combination with another agent, until such time that one or more biologically
rational combinations demonstrate an effect.
31 To qualify for a deferral, the applicant must submit (i) certification of the grounds for deferring the assessments or
reports on the investigation; (ii) a pediatric study plan as described in section 505B(e) of the FD&C Act;
(iii) evidence that the studies are being conducted or will be conducted with due diligence and at the earliest possible
time; and (iv) a timeline for the completion of such studies. Section 505B(a)(4)(A)(ii) of the FD&C Act.

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o 	until additional clinical evidence of safety or effectiveness of the drug has been
collected.
• 	Until such time that an appropriate pediatric formulation for investigational purposes
is available, provided there has been due diligence in formulation development.
• 	If the drug is ready for approval for use in adults before the pediatric study(ies) is
completed.
IV. 	GLOBAL IMPLICATIONS AND INTERNATIONAL COLLABORATION
FDA recognizes the global scope of drug development and strongly encourages all stakeholders
to support internationally coordinated and collaborative approaches to development of drugs to
treat cancers in pediatric patients. Due to the rarity of pediatric cancers, which are frequently
being subdivided into even rarer subpopulations based on underlying molecular features,
international collaboration is increasingly important for facilitating the development of new
treatments. Furthermore, the number of investigational drugs of potential interest far exceeds the
number of pediatric patients available to enroll in clinical trials. Therefore, global coordination
is increasingly important for prioritizing drugs of interest in general and for specific cancers in
pediatric patients, especially for drugs of the same class, for early pediatric evaluation. This aids
in preventing duplication of studies and competition for scarce patients and limiting unnecessary
exposure of pediatric patients to investigational drugs.
The following opportunities exist to facilitate coordinated, global approaches to pediatric
development:
A. 	Pediatric Cluster Teleconferences
• 	Informal at least monthly teleconferences between the FDA and the European
Medicines Agency (EMA), together with representatives from Health Canada, the
Japanese Pharmaceutical and Medical Devices Agency, and the Australian
Therapeutic Goods Administration coordinated by FDA’s Office of Pediatric
Therapeutics.
• 	Provide opportunities for high-level scientific discussion of issues relating to
development of specific drug products. Relevant documents and information are
shared between participating regulatory agencies under the terms of existing
confidentiality agreements.
• 	Regulatory agencies may request that a particular topic be placed on the agenda for
discussion. Sponsors are informed of specific comments resulting from the
discussions and may receive details of the discussions after the teleconference.
• 	Sponsors also can submit a request to either the FDA (to either the appropriate review
division or office or the Oncology Center of Excellence Pediatric Oncology Program)
or EMA that their drug product – or more generally, the appropriateness of potential
indications by drug class – be considered for discussion.

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B. 	Common Commentary Process
• 	Established by FDA and the EMA to inform sponsors of the outcome of scientific
exchanges related to select drug products or topics discussed at Pediatric Cluster
teleconferences.
• 	Is intended to facilitate early sponsor interactions with the relevant agencies and
neither alter nor replace routine review procedures.
• 	FDA recommends this mechanism for high level scientific review of early pediatric
development plans and reaching consensus, when possible, to facilitate alignment of
advice to sponsors seeking uniformity of design concepts for iPSPs and Pediatric
Investigation Plans (PIPs).
• 	Applies to drug products for which a pediatric development plan is contemplated or
has been submitted to both FDA and the EMA and is under review, preferably early
in the regulatory process.
• 	FDA or EMA can nominate a product or topic for discussion.
• 	FDA has assumed primary responsibility for drafting a document that summarizes the
discussion and generally includes recommendations. After review and clearance by
both agencies, the Common Commentary document is shared with the sponsor. This
document is nonbinding, and it does not provide final regulatory decisions.
• 	Sponsors may advise the appropriate review division or office or the OCE Pediatric
Oncology Program that they wish to have their product’s iPSP (and PIP, if already
submitted to EMA) and their proposed global pediatric development be the subject of
a Common Commentary. Sponsors may seek FDA clarification following receipt of
the Common Commentary by requesting a Type C meeting with the review division
or office.
C. 	Formal Parallel Scientific Advice (PSA)
• 	Provides formal mechanism for provision of concurrent exchange of advice from
EMA assessors and FDA reviewers with sponsors on scientific issues to optimize
drug development.
• 	Consideration of PSA and a request for this process should be made to the appropriate
review division or office early and well in advance of the submission of the iPSP in
order to help avoid any possible delay in submission of the NDA/BLA due to the
failure to reach agreement on the iPSP.
• 	Information regarding the PSA procedure, including how to apply, is available.32
Additionally, FDA encourages participation in international multi-stakeholder meetings such as
the Pediatric Strategy Forums organized by the ACCELERATE Platform 33 and other
international meetings or conferences which bring sponsors, investigators, patient advocates, and
32 GENERAL PRINCIPLES EMA-FDA PARALLEL SCIENTIFIC ADVICE (HUMAN MEDICINAL
PRODUCTS)
https://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofGlobalRegulatoryOperationsandPolicy/Officeof
InternationalPrograms/UCM557100.pdf.
33 For additional information, see https://www.accelerate-platform.eu/paediatric-strategy-forum/ (accessed May 18,
2021).

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regulators together to discuss development strategies for specific pediatric cancers in the context
of the number of investigational drugs available for assessment and the highly variable unmet
medical needs of distinct pediatric populations with specific childhood cancers. We recommend
stakeholders, including sponsors, investigators, and patient advocates consider coordinating early
multi-stakeholder input to inform decision-making related to the initial pediatric clinical
evaluation of appropriate investigational drugs to both avoid unnecessary duplication and
provide an efficient framework for a longer-term development strategy of promising new drugs.
An international perspective on clinical trial feasibility and the extent of unmet clinical need, as
well as the scientific rationale for early evaluation and continued development of a class of
molecularly targeted products or individual investigational drugs may help inform appropriate
development plans of promising drugs for children with cancer globally.