Drugs for the Treatment of Partial Onset Seizures: Extrapolation of Efficacy from Adults to Pediatric Patients 1 Month of Age and Older

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

Drugs for Treatment of Partial
Onset Seizures: Extrapolation of
Efficacy from Adults to Pediatric
Patients 1 Month of Age and Older
Guidance for Industry
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
August 2024
Clinical Pharmacology
Revision 1

Drugs for Treatment of Partial
Onset Seizures: Extrapolation of
Efficacy from Adults to Pediatric
Patients 1 Month of Age and Older
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: druginfo@fda.hhs.gov
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
August 2024
Clinical Pharmacology
Revision 1

TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 1
III. 	DEVELOPMENT CONSIDERATIONS ........................................................................ 2
A. 	Formulation Development............................................................................................................. 2
B. 	Efficacy Considerations ................................................................................................................. 2
C. 	Clinical Pharmacology and Dosing Considerations .................................................................... 3
D. 	Safety Considerations .................................................................................................................... 3

Contains Nonbinding Recommendations
1
Drugs for the Treatment of Partial Onset Seizures:
Extrapolation of Efficacy from Adults to Pediatric Patients
1 Month of Age and Older
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
This guidance provides recommendations to sponsors on the clinical development of drugs for
the treatment of partial onset seizures (POS) in pediatric patients. Specifically, this guidance
addresses FDA’s current thinking regarding clinical development programs that can support
extrapolation of the efficacy of drugs approved for the treatment of POS in adults to pediatric
patients 1 month of age and older. This guidance does not address the development of drugs to
treat other types of seizures.
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
Historically, because evidence to support an extrapolation approach was not available, FDA has
required, under section 505(d) of the Federal Food, Drug, and Cosmetic Act, that sponsors
establish efficacy for the treatment of POS in pediatric patients by performing one or more
adequate and well-controlled clinical studies in pediatric patients. The doses in these pediatric
studies were generally based on body weight and age, in an effort to attain blood concentrations
1 This guidance has been prepared by the Division of Neurology Products and the Division of Clinical
Pharmacology I in the Center for Drug Evaluation and Research at the Food and Drug Administration. You may
submit comments on this guidance at any time. Submit comments to Docket No. FDA-2017-D-6821 (available at
https://www.regulations.gov/docket?D=FDA-2017-D-6821). See the instructions in that docket for submitting
comments on this and other Level 2 guidances.

Contains Nonbinding Recommendations
2
similar to those found to be effective in adults, and were also informed by safety and tolerability
data from open-label studies in the pediatric population.
Efficacy can be extrapolated from adults to pediatric patients when it is reasonable to assume
that children, compared with adults, have a similar progression of disease, similar response of
disease to treatment, and similar exposure-response relationship.2 After excluding children with
POS associated with epileptic encephalopathies, such as Lennox-Gastaut syndrome, the
pathophysiology of POS appears similar in adults and pediatric patients 1 month of age and
older.3 Clinical studies of drugs for the treatment of POS in pediatric patients, some of which
enrolled patients as young as 1 month of age, have shown a response to treatment (reduction in
seizure frequency) similar to the response to treatment seen in adults. Initial systematic and
quantitative analyses conducted by FDA, using data from clinical studies of drugs with a variety
of putative mechanisms of action approved for the treatment of POS in both adults and pediatric
patients, have shown that the relationship between exposure and response (reduction in seizure
frequency) is similar in adults and pediatric patients 4 years of age and older. Subsequent
evaluation by FDA determined that POS are readily identifiable in pediatric patients down to 1
month of age and are phenomenologically and pathophysiologically very similar to those in older
patients. These analyses and observations have allowed FDA to conclude that the efficacy of
drugs approved for the treatment of POS can be extrapolated from adults to pediatric patients 1
month of age and older.
III. 	DEVELOPMENT CONSIDERATIONS
A. 	Formulation Development
Children may differ from adults in many aspects of pharmacotherapy, including feasibility of
routes of drug administration and taste preferences. It is therefore essential for sponsors to
formulate pediatric drugs to best suit a child’s age, size, and physiologic condition. FDA
encourages sponsors to explore innovative approaches to pediatric formulation development and
testing.
B. 	Efficacy Considerations
As noted above, FDA has concluded that the efficacy of drugs approved for the treatment of POS
in adults can be extrapolated to pediatric patients 1 month of age and older. This conclusion does
not apply to the treatment of other types of seizures.
2 See the guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological
Products (May 1998). See also the draft guidances for industry General Clinical Pharmacology Considerations for
Pediatric Studies for Drugs, Including Biological Products (September 2022) and E11A Pediatric Extrapolation
(August 2022). When final, these guidances will represent the FDA’s current thinking on this topic. 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.
3 Pellock JM, Carman WJ, Thyagarajan V, Daniels T, Morris DL, and D’Cruz O, 2012, Efficacy of Antiepileptic
Drugs in Adults Predicts Efficacy in Children: A Systematic Review, Neurology, 79(14):1482–1489.

Contains Nonbinding Recommendations
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C. 	Clinical Pharmacology and Dosing Considerations
To support extrapolation, blood concentrations of active drug and metabolites should be obtained
from an adequately designed pharmacokinetic and tolerability study in patients 1 month to 16
years of age. The study should include an appropriate distribution of pediatric patients across this
age range and be designed to characterize adequately the acute tolerability over a range of doses
that covers drug concentrations known to be effective in adults.
Simulations should be performed to select doses expected to achieve exposures similar to those
in adults. The sample size and sampling scheme should be planned carefully to enable
characterization of pharmacokinetics with adequate precision.4 Pharmacokinetic data from that
study should be used to determine pediatric doses and regimens that provide drug exposure
similar to that known to be effective in adult patients with POS. Sponsors should share the
results of this analysis with FDA before initiating the open-label safety studies described below.
D. 	Safety Considerations
Sponsors should conduct clinical studies to characterize adequately the safety of the drug in
pediatric patients 1 month of age and older with POS, with all ages well-represented. Such
studies can be open label in design. In general, a minimum of 100 pediatric patients should be
exposed to the drug for at least 6 months of treatment, although the specific study characteristics
should be determined on a case-by-case basis, depending on the expected and emerging safety
profile of the drug. Dosing levels in these safety studies should be at exposures similar to those
found to be effective in the pediatric population and that are proposed for labeling, based on the
extrapolation described above. Blood concentrations of the drug and its active major metabolites
should be quantified whenever severe or serious adverse events occur in patients enrolled in the
study.
4 Wang Y, Jadhav PR, Lala M, and Gobburu JV, 2012, Clarification on Precision Criteria to Derive Sample Size
When Designing Pediatric Pharmacokinetic Studies, J Clin Pharmacol, 52(10):1601–1606.