Drugs for Treatment of Partial 
Onset Seizures: Full Extrapolation 
of Efficacy from Adults to Pediatric 
  
Patients 2 Years 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) 
 
September 2019 
Clinical Pharmacology/Clinical 
 
   
Drugs for Treatment of Partial 
Onset Seizures: Full Extrapolation 
of Efficacy from Adults to Pediatric 
Patients 2 Years 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) 
 
September 2019 
Clinical Pharmacology/Clinical 
 
   
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 .................................................................... 2 
D.  Safety Considerations .................................................................................................................... 3 
  Contains Nonbinding Recommendations 
 
Drugs for the Treatment of Partial Onset Seizures: Full 
Extrapolation of Efficacy from Adults  
to Pediatric Patients 2 Years 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 FDAs 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 2 years of age and older. This guidance does not address clinical development programs 
for the treatment of POS in pediatric patients younger than 2 years of age. This guidance does 
not address the development of drugs to treat other types of seizures. 
 
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 
 
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 
similar to those found to be effective in adults. Selection of doses was also informed by safety 
and tolerability data from open-label studies in the pediatric population. 
 
                                                 
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. 
  1  Contains Nonbinding Recommendations 
 
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 2 years 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 2 years of age, have shown a response to treatment (reduction in 
seizure frequency) similar to the response to treatment seen in adults. Systematic and quantitative 
analyses conducted by FDA, using data from clinical studies of drugs 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. These drugs have a variety of putative mechanisms of action. 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 2 years 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, drug-related toxicity, and taste preferences. It is therefore essential 
for sponsors to formulate pediatric drugs to best suit a childs 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 2 years of age and older. This conclusion does 
not apply to the treatment of POS in pediatric patients younger than 2 years of age or to the 
treatment of other types of seizures. 
 
C.  Clinical Pharmacology and Dosing Considerations 
 
To support extrapolation, blood concentrations of active drugs and metabolites should be 
obtained from an adequately designed pharmacokinetic and tolerability study in patients 2 to 16 
years of age. The study should include an appropriate distribution of pediatric patients across this 
                                                 
2 See the guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological 
Products (May 1998).  See also the pediatric study planning and extrapolation algorithm in the draft guidance for 
industry General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and Biological Products 
(December 2014). When final, this guidance will represent FDAs 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 DCruz O, 2012, Efficacy of Antiepileptic 
Drugs in Adults Predicts Efficacy in Children: A Systematic Review, Neurology; 79(14):14821489. 
  2  Contains Nonbinding Recommendations 
 
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 dose 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 
 
Safety data generally cannot be extrapolated from adults to children. Therefore, sponsors should 
conduct clinical studies to characterize adequately the safety of the drug in pediatric patients 2 
years 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 or above those determined to be effective in the 
pediatric population, 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):16011606. 
  3