Head Lice Infestation: 

Developing Drugs for 

Topical Treatment 

Guidance for Industry 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER)
  
 
October 2016 

Clinical/Medical 

   
Head Lice Infestation: 

Developing Drugs for 

Topical Treatment 

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 
 
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Silver Spring, MD  20993-0002  

Phone: 855-543-3784 or 301-796-3400;  Fax: 301-431-6353;  Email: druginfo@fda.hhs.gov 
 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER)
  
 
October 2016 

Clinical/Medical 

 
   
TABLE OF CONTENTS 
 
 
I.   INTRODUCTION............................................................................................................. 1
  
II.   BACKGROUND ............................................................................................................... 2
  
III.   DEVELOPMENT PROGRAM ....................................................................................... 2
  
A.   General Considerations .................................................................................................................2
  
1.  Early Phase Clinical Development Considerations .........................................................................2
  
2.  Drug Development Population .........................................................................................................4
  
3.  Entry Criteria ...................................................................................................................................4
  
4.  Safety ................................................................................................................................................4
  
a.   Special safety studies.................................................................................................................5
  
b.   Drug-drug interactions ..............................................................................................................6
  
5.  Clinical Pharmacology .....................................................................................................................6
  
B.   Specific Efficacy Trial Considerations .........................................................................................7
  
1.  Trial Design......................................................................................................................................7
  
2.  Trial Population ...............................................................................................................................7
  
3.  Entry Criteria ...................................................................................................................................7
  
4.  Randomization, Stratification, and Blinding ....................................................................................8
  
5.  Specific Populations .........................................................................................................................8 
 
a.   Pediatric.....................................................................................................................................8 
 
b.   Pregnant and lactating women...................................................................................................8 
 
c.   Geriatric.....................................................................................................................................9 
 
6.  Dose Selection ..................................................................................................................................9 
 
7.  Choice of Comparators ....................................................................................................................9
  
8.  Efficacy Endpoints ............................................................................................................................9 
 
9.  Trial Procedures and Timing of Assessments ................................................................................10 
 
10.   Endpoint Adjudication ............................................................................................................... 10 
 
11.   Statistical Considerations .......................................................................................................... 10 
 
12.   Accelerated Approval (Subpart H) Considerations ...................................................................11 
 
13.   Risk-Benefit Considerations....................................................................................................... 11 
 
C.   Other Considerations ................................................................................................................... 11 
 
1.  Relevant Nonclinical Considerations............................................................................................. 11 
 
2.  Labeling Considerations ................................................................................................................ 11 
 
 
  Contains Nonbinding Recommendations 
Head Lice Infestation: 

Developing Drugs for Topical Treatment 

1
 
Guidance for Industry  
 
 
 
 
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 assist sponsors in the clinical development of drugs for the 
treatment of head lice infestation.2  Specifically, this guidance addresses the Agencys current  
thinking regarding the overall development program and clinical trial designs of drugs to support 
approval of an indication for topical treatment of head lice infestation.  The information 
presented will help sponsors plan clinical trials, design clinical protocols, and conduct and 
appropriately monitor clinical trials.  Development plans should be discussed with the review 
division before initiating trials to ensure that the trial design meets defined objectives.  
 
This guidance does not contain discussion of the general issues of statistical analysis or clinical 
trial design. Those topics are addressed in the ICH guidances for industry E9  Statistical 
Principles for Clinical Trials and E10 Choice of Control Group and Related Issues in Clinical 
Trials, respectively.3  This guidance focuses on specific drug development and trial design issues 
that are unique to the study of head lice infestation.   
 
This guidance also does not contain discussion of nonclinical or chemistry, manufacturing, and 
controls issues. See the ICH guidance for industry M3(R2)  Nonclinical Safety Studies for the 
Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals.  
 
                                                 
1 This  guidance has been  prepared by the Division of  Dermatology and Dental Products in  the Center for  Drug  
Evaluation and Research at the Food and Drug Administration.   
 
2 For the purposes of this guidance, all references to drugs include human drugs and not therapeutic biological  
products  unless otherwise specified.  
 
3  We  update  guidances periodically.  To make sure you  have the most recent version of a guidance, check the FDA  
Drugs guidance Web page  at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
1 
 Contains Nonbinding Recommendations 
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 
 
Head lice infestation is characterized by infestation of the scalp and scalp hair by a wingless 
parasitic insect, the human head louse, Pediculus humanus capitis. Head lice live on the hair and 
feed on the scalp by consuming a blood meal.4  
 
Head lice infestation is widespread, affecting both children and adults.  In the United States it is 
estimated that between 6 and 12 million infestations occur each year among children 3 to 11 
years of age.5    
 
There are many FDA-approved drugs (including prescription and nonprescription drugs) for the 
treatment of head lice infestation, but genetic resistance of lice to lindane and to the most 
commonly used treatments, pyrethroids, is not uncommon in the United States;6,7 thus 
development of additional drugs for this indication is encouraged. 
 
 
III.  DEVELOPMENT PROGRAM 
 
A.  General Considerations 
 
1.  Early Phase Clinical Development Considerations   
 
In early phase clinical development the components of the investigational drug should be defined 
and all active moieties identified.  If two or more active components are identified, it should be 
demonstrated that each active component makes a contribution to the claimed effects and the 
dosage of each active component is such that the combination is safe and effective for the 
intended patient population (see 21 CFR 300.50). 
 
                                                 
4  Jacobson, CC and EA Abel, 2007, Periodic Synopsis:  Parasitic Infections, J Am  Acad Dermatology, 56:1026-
1043. 
 
5 See the Epidemiology & Risk Factors  Web page (located under Parasites  Lice  Head  Lice) on the Centers for 
Disease Control and Prevention Web site at http://www.cdc.gov/parasites/lice/head/epi.html.  
 
6 Lebwohl, M, L Clark, and J Levitt, 2007, Therapy for Head Lice Based  on  Life Cycle, Resistance, and Safety, 
Pediatrics, 119:965-974.  
 
7 Burkhart, CN, CG Burkhart, and DS Morell, 2012, Head Lice, in  Dermatology, edited  by JL Bolognia, JL Jorizzo,  
and JV Schaffer, 3rd edition, published  by Elsevier, Chapter 84, page 1426. 
2 
 Contains Nonbinding Recommendations 
If the drug contains more than one active ingredient, the sponsor can consider in vitro studies to 
assess the contribution to efficacy of each of the active ingredients.  This issue should be  
discussed with the Agency early in clinical development. 
 
Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new 
active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of 
administration are required to contain an assessment of the safety and effectiveness of the drug 
for the claimed indication(s) in pediatric patients unless this requirement is waived, deferred, or 
inapplicable. 
 
Head lice infestation is primarily a pediatric disease.  Sponsors are encouraged to discuss 
pediatric drug development with the FDA early in the course of clinical development, including 
appropriate pharmacokinetic (PK) trials in pediatric subjects to support dose selection and the 
recommended size of the preapproval safety database in children.  Under PREA, a waiver to 
provide a pediatric assessment may be granted if certain criteria are met.  Historically, studies in 
patients younger than 6 months of age for the treatment of head lice infestation have been waived  
most often because the studies were impossible or highly impracticable.  Under certain 
circumstances, there may be other reasons for waiver (e.g., there was evidence of lack of 
meaningful therapeutic benefit over existing treatments and was not likely to be used by a 
substantial number of patients in that age group or there was strong evidence suggesting the drug 
is ineffective or unsafe in that age group).  If studies for any pediatric age group are waived for 
safety concerns, the safety concern must be included in product labeling.8  Sponsors are required 
to submit an initial pediatric study plan no later than 60 days after an end-of-phase 2 meeting.9   
See the draft guidance for industry Pediatric Study Plans:  Content of and Process for 
Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans for 
information regarding the content of and process for submission of an initial pediatric study 
plan.10  
 
Trials to identify an appropriate (safe and effective) dose are an important component of phase 2 
development for topical treatment of head lice infestation.  A dose-response trial conducted 
during early phase clinical development to assess safety and efficacy can help ensure that the 
most appropriate dose regimen is selected for phase 3 development.  For additional information 
on the FDAs current thinking regarding dose response, see the ICH guidance for industry 
E4 Dose-Response Information to Support Drug Registration and the guidances for industry 
Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products and  
Exposure-Response Relationships  Study Design, Data Analysis, and Regulatory Applications.   
 
                                                 
8 See PREA  (Public Law 108-155;  sections 505B(a)(4)(D) and 505B(b)(2)(D) of the Federal Food, Drug, and  
Cosmetic Act (FD&C Act); 21 U.S.C. 355c). 
 
9 See PREA  (Public Law 108-155;  section 505B(e)(2)(A) of the FD&C Act; 21 U.S.C. 355c) as amended  by the 
Food and Drug Administration Safety and Innovation Act (Public Law 112-144).  
 
10  When final, this guidance will represent the FDAs current  thinking on this topic.   
3 
 Contains Nonbinding Recommendations 
2.  Drug Development Population  
 
The trial population should be representative of the target population for which the drug is 
intended for use in clinical practice (e.g., reflective of the age, race, and sex of the population 
with head lice infestation in the United States).  Pediatric subjects should be evenly distributed 
across age groups. Inclusion of younger age groups would be dependent upon safety findings for 
the investigational drug. Geographical diversity is also important for the treatment of head lice 
infestation because resistance patterns to some drugs vary by location.   
 
Although head lice infestation (P. capitis) is primarily a disease of the pediatric population, it 
may be appropriate to obtain safety and efficacy data in adults before proceeding with studies in 
the pediatric population. See the ICH guidance for industry E11  Clinical Investigation of 
Medicinal Products in the Pediatric Population. 
 
If the sponsor plans to conduct trials outside of the United States, the sponsor should consider 
factors that may affect the acceptability of such data for drug approval in the United States.  
Sufficient information should be provided to demonstrate that data from clinical trials conducted 
outside of the United States are applicable to and will predict the clinical outcomes in U.S. 
patients (see 21 CFR 314.106). See the ICH guidance for industry E5 Ethnic Factors in the 
Acceptability of Foreign Clinical Data and the guidance for industry Collection of Race and 
Ethnicity Data in Clinical Trials. 
 
3.  Entry Criteria  
 
For general information regarding the performance of trials to evaluate efficacy, see the guidance 
for industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological 
Products.  See also sections III.A.2., Drug Development Population, and III.B., Specific Efficacy 
Trial Considerations, for additional discussion.  The inclusion and exclusion criteria should be 
sufficiently broad to allow enrollment of a population that will be representative of that 
anticipated with proposed labeling (e.g., representative of real-world use).   
 
4.  Safety  
 
Both local and systemic safety information (e.g., adverse events and laboratory data) should be 
collected during clinical trials.  All subjects should be evaluated for safety at the time of each 
trial visit or assessment, regardless of whether the investigational drug has been discontinued for 
safety. Generally, all adverse events should be followed until resolution, even if time on clinical 
trial would otherwise have been completed.  
 
Local safety assessment of the skin/scalp (with careful attention to the adjacent skin such as the 
forehead, neck, and ears) and eyes should include evaluation for the presence of erythema, 
edema, pustules, excoriation, and a query for pruritus (at baseline and post-treatment visits).  
This evaluation should occur at intervals most likely to capture any safety signal.  The timing of 
evaluation may be affected by factors such as the type of drug being studied and the type of 
reaction that is expected. 
 
4 
 Contains Nonbinding Recommendations 
Evaluation of systemic safety should include monitoring for systemic adverse events, laboratory 
monitoring, physical exam/vital signs, and where appropriate (e.g., for a new molecular entity in 
the absence of PK data under maximal use conditions) cardiac safety monitoring such as 
electrocardiogram monitoring.   
 
A maximal use PK trial should be conducted to assess systemic bioavailability and safety.  For 
further information, see section III.A.5., Clinical Pharmacology. 
 
A number of important safety issues for drugs already approved for treating head lice infestation 
have been identified, for example:  
 
	   Neurotoxicity:  The treatment may achieve efficacy through effects on the insects 
nervous system.  Systemic absorption of the drug could raise concern about effects on the 
human nervous system. 
 
	   Neonatal toxicity:  The treatment may contain benzyl alcohol.  There is a risk of gasping 
syndrome if benzyl alcohol is used in neonates and low birth weight infants.   
 
	   Inhibition of acetylcholinesterase:  An approved drug (malathion) inhibits 
acetylcholinesterase, and its systemic absorption may increase the risk of bradycardia,  
respiratory distress, and diarrhea.  
 
During drug development the sponsor should also consider potential safety issues such as: 
 
 	  Teratogenicity:  The risk of teratogenicity should be evaluated.  See ICH M3(R2). 
Measures to reduce the risk for pregnancy exposure should be employed for both 
caregivers, who administer the investigational drug to pediatric subjects, and subjects 
who are of reproductive potential. 
 
 	  Arrhythmogenic potential:  See the ICH guidance for industry E14  Clinical Evaluation 
of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic 
Drugs.   
 
 	  Medication errors such as ingestion of the intended topical drug:  Preventive measures 
such as child-resistant packaging and/or orifice narrowing should be considered early in 
drug development.  
 
 	  Environmental concerns:  Because the active ingredients in some head lice drugs are also 
insecticides, the effect of the introduction of these drugs and their metabolites into the 
environment should be anticipated and evaluated.  See the guidance for industry 
Environmental Assessment of Human Drug and Biologics Applications. 
 
a.  Special safety studies  
 
For topical drugs, dermal safety studies with the to-be-marketed drug may be needed to provide 
information regarding cumulative irritancy, contact sensitization, photoxicity, and photo-contact 
allergic potential.  
5 
 Contains Nonbinding Recommendations 
 
b.  Drug-drug interactions 
 
The potential for drug-drug interactions should be adequately addressed during development.  
For further information, see the draft guidance for industry Drug Interaction Studies  Study 
Design, Data Analysis, Implications for Dosing, and Labeling Recommendations.11  
 
5.  Clinical Pharmacology  
 
PK trials to assess systemic absorption may be needed unless there is a waiver of in vivo 
bioavailability studies, which is rarely granted.  Because of the variable dosing nature of topical 
drugs, the FDA recommends that trials of the in vivo assessment of systemic exposure be done 
under so-called maximal use  conditions.12  The recommended elements of such a maximal use 
PK trial are as follows:  
 
1. 	  A formulation identical to the clinically studied/to-be-marketed formulation should be 
used. 
 
2. 	  The trial should be done in an adequate number of subjects at upper end of severity of 
lice infestation (e.g., at least three live lice present at enrollment and moderate 
pruritus/excoriation of scalp) that is expected to be included in both the clinical program  
and the anticipated approved indication. Steps should be taken to ensure that the target 
patient population (e.g., age, sex, race) is adequately represented.  The FDA recommends 
enrollment be stratified by age to ensure a sufficient number of younger subjects are 
enrolled. 
 
3. 	  The topical dosing regimen selected should represent the maximal dosing anticipated in 
both phase 3 trials and in the proposed labeling for the following: 
 
	   Use of highest proposed strength 
	   Amount applied  
	   Method of application and site preparation 
	   Frequency of dosing 
	   Duration of treatment  
 
4.	   The analytical method should be properly validated for both parent compound and 
metabolites.  
 
The objective of this trial is to maximize those elements affecting dermal penetration to assess 
systemic bioavailability and systemic safety of the drug.  The FDA recommends, when possible, 
that the resulting PK data be analyzed using standard PK metrics (e.g., area under the 
                                                 
11  When final, this guidance will represent the FDAs current  thinking on this topic.  
 
12 Bashaw, ED, T Tran, C Shukla, and X Liu, 2015, Maximal Usage Trial:  An Overview  of the Design  of Systemic 
Bioavailability Trial for Topical Dermatological Products, Therapeutic Innovation & Regulatory Science, Vol. 49(1) 
108-115. 
6 
 Contains Nonbinding Recommendations 
concentration versus time curve, maximum concentration (C ), time at which C  occurs, half-
max max
life).  It is also recommended that the trial protocols incorporate evaluations for cutaneous safety. 
 
B.  Specific Efficacy Trial Considerations 
 
The trial protocol should take into consideration the following elements. 
 
1.  Trial Design 
 
In general, sponsors should conduct two randomized, double-blinded, controlled trials to 
establish efficacy and safety of a drug for the treatment of head lice infestation in the intended 
population. A commonly used design compares the investigational drug to vehicle alone.  In a 
vehicle-controlled design, potential influences on the course of the disease other than those 
arising from the pharmacologic action of the investigational drug can be controlled via 
randomization and blinding.  See also section III.B.9., Trial Procedures and Timing of 
Assessments, for additional comments relating to trial design, and refer to the guidance for 
industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products.   
 
If the investigational drug has clinically significant potential risks (e.g., neurotoxicity), an active 
control may be appropriate to ensure that the investigational drug has a clinically meaningful 
benefit (e.g., superior efficacy or comparable efficacy with more favorable safety profile) when 
compared to an approved topical treatment for head lice infestation.  In active-controlled clinical 
trials, the comparator should be an FDA-approved drug, used according to approved labeling.  
 
Use of a lice comb device as part of the treatment regimen could affect efficacy.  When a device 
such as a dedicated comb is to be used, the sponsor should submit its specifications to the 
investigational new drug application as early as is feasible.  
 
2.  Trial Population 
 
The population studied should include pediatric subjects with an age group distribution reflecting 
the fact that the highest incidence of head lice infestation is found in children aged 3 to 11 years.  
Depending upon safety findings, the lower boundary of age studied, generally younger than 
6 months, should be as low as that in which use is intended to occur.  See also sections III.A.1., 
Early Phase Clinical Development Considerations, and III.A.2., Drug Development Population.  
 
3.  Entry Criteria 
 
Entry criteria should specify a minimum baseline level of infestation.  Index subjects are the 
primary population to be evaluated for efficacy and should have an active head lice infestation, 
defined as at least three live lice (adults and/or nymphs) present on the scalp and/or hair.  Index 
subjects are defined as the youngest household members presenting with an active head lice 
infestation. Household members, to be considered for trial entry, should have an active head lice 
infestation defined as at least one live louse present on the scalp and/or hair. 
 
7 
 Contains Nonbinding Recommendations 
Subjects with the following characteristics should be excluded from trials for head lice 
infestation: 
 
 	  Presentation at the treatment site with visible skin/scalp condition(s) that are not 
attributable to head lice infestation and that in the opinion of the investigative personnel 
will interfere with safety and/or efficacy evaluations 
 
	   Recent (e.g., within 7 days) treatment for head lice, including nonprescription, home 
remedy, and/or prescription treatments 
 
Because the population studied is expected to include pediatric subjects, the sponsor should 
employ age-appropriate assent/informed consent.  
 
4.  Randomization, Stratification, and Blinding 
 
Ideally, trials should be multicenter, well-controlled, and double-blinded.  Randomization and 
blinding are important to minimize biases.  If blinding of both subject and evaluator is not 
possible, sponsors should discuss potential biases with the FDA and how these biases will be 
addressed. 
 
If an active-controlled trial design is chosen, challenges to blinding may occur and the following 
additional processes may be needed to minimize bias:   
 
 	  If the labeled treatment regimen for the active control is different from that for the 
investigational drug, the time and geographical place of drug application can be masked 
from the evaluators of the trial 
 
 	  If the active control treatment involves a procedure, such as combing, that is not part of 
the proposed treatment regimen under study, or if the proposed drug treatment involves a 
procedure that is not part of approved labeling for the active control, an additional 
treatment arm that involves use of both the procedure and the relevant drug (proposed 
treatment or active control, respectively) can be included 
 
For details of randomization and stratification, see section III.B.11., Statistical Considerations. 
 
5.  Specific Populations 
 
a.  Pediatric  
 
See section III.A.1., Early Phase Clinical Development Considerations, for information relating 
to pediatric considerations. 
 
b.  Pregnant and lactating women 
 
Fertility and embryo fetal development studies in animals should be completed before phase 3 
trials are initiated. Results of such studies generally should be included in labeling.  
Additionally, available information regarding the use of the drug in pregnant women should be 
8 
 Contains Nonbinding Recommendations 
included in labeling. Sponsors should be advised of labeling requirements in other guidance for 
pregnancy, lactation, and females and males of reproductive potential.13    
 
Information on the safety of the drug during lactation also should be included in labeling.  
Information on conducting lactation studies, when necessary, is addressed in other guidance.14   
 
Caregivers may be exposed to the drug during application to younger pediatric subjects.  Risks of 
exposure to caregivers who are pregnant or lactating should be addressed and included in 
labeling, if appropriate. 
 
c.  Geriatric  
 
If conclusions are to be made regarding drug safety and efficacy in the geriatric population, a 
sufficient number of subjects 65 years of age and older should be evaluated at the level of 
exposure (dose and duration) proposed for use.  See the ICH guidance for industry E7  Studies in 
Support of Special Populations: Geriatrics. 
 
6.  Dose Selection 
 
See section III.A.1., Early Phase Clinical Development Considerations,  for a more detailed 
discussion of dose-ranging.  
 
7.  Choice of Comparators  
 
See section III.B.1., Trial Design, for a discussion of comparators. 
 
8.  Efficacy Endpoints  
 
The primary efficacy measure should be the presence or absence of live lice in index subjects.  
 
The primary efficacy endpoint should be dichotomized to success or failure with success defined 
as the absence of live lice and failure defined as the presence of live lice.  Specifically, success 
should be defined as follows: 
 
 	  The proportion of index subjects in the enrolled households who are lice free (no live 
lice, adults or nymphs) 14 days after the last treatment   
 
                                                 
13 See the draft guidance for industry Pregnancy, Lactation, and Reproductive Potential:  Labeling for Human 
Prescription  Drug and Biological Products  Content and Format.   When  final, this guidance will represent the 
FDAs current  thinking on this topic.  
 
14 See the draft guidance for industry Clinical  Lactation Studies  Study Design, Data Analysis, and  
Recommendations for Labeling. When final, this guidance will represent the FDAs current thinking on this topic.   
9 
 Contains Nonbinding Recommendations 
9.  Trial Procedures and Timing of Assessments 
 
The time point to evaluate efficacy should be based on the life cycle of the head louse.  Because 
nits hatch in a range of 6 to 12 days after being laid,15,16 selection of a time point 14 days after 
the last treatment to evaluate for efficacy minimizes the likelihood of missing late-hatching lice.  
 
The assessment of presence or absence of live lice should be performed by a trained evaluator, 
with a minimum agreed-upon time for lice examination in the event that lice are not immediately 
identified. The actual time spent in examination should be documented on the case report form. 
 
Because approved drugs for head lice treatment are available, if a vehicle-controlled trial will be 
conducted, its design should include an early removal option for rescue treatment of subjects 
who have live lice after the last treatment and evaluation.  Household members who have active 
head lice infestation, defined as at least one live louse present on the scalp and/or hair, should 
receive the same treatment as index subjects.  
 
Trial procedures in phase 3 trials should conform as closely as possible to expected real-world 
use (e.g., the caregiver should apply the medication at home rather than investigator application 
in the clinic) so that results from pivotal trials will be generalizable to the postmarketing setting.  
 
The use of drugs for the treatment of head lice infestation occurs within the context of an overall 
lice management program.  Trial design should include appropriate instructions to subjects such 
as: 
 
 	  Wash (in hot water) or dry-clean all recently worn clothing, hats, used bedding, and 
towels  
 
 	  Wash (in hot water) personal care items such as combs, brushes, and hair clips 
 
 	  Use a fine-tooth comb or special nit comb to remove nits and dead lice 
 
10.  Endpoint Adjudication 
 
In general, endpoint adjudication is not needed for topical drugs intended for the treatment of 
head lice infestation.  
 
11.  Statistical Considerations 
 
Because treatment efficacy could be affected by household members with an active head lice 
infestation, randomization should be done at the household level, where the index subject and all 
eligible household members would receive the same treatment.  The primary population for the 
                                                 
15 Lebwohl, M, L Clark, and J Levitt, 2007, Therapy for Head Lice Based  on  Life Cycle, Resistance, and Safety, 
Pediatrics, 119:965-974. 
 
16 van  der Wouden, JC, T Klootwijk, L Le Cleach et al., 2011, Interventions  for Treating Head Lice (Protocol), The 
Cochrane Library, Issue 10.   
10 
  Contains Nonbinding Recommendations 
evaluation of efficacy is the index subjects; therefore, the intent-to-treat population should be 
defined as all index subjects randomized and dispensed treatment medication.  
 
Because there may be regional or investigator-related factors that may affect assessment of 
efficacy (such as drug resistance patterns of head lice or investigator skill), evaluating center-to-
center variability is recommended for appropriate interpretation of trial findings.  Therefore, 
centers should enroll a reasonable number of subjects to allow for a meaningful assessment of 
center-to-center variability.  
 
12.  Accelerated Approval (Subpart H) Considerations  
 
Head lice infestation is not a serious or life-threatening condition; therefore, accelerated 
approval is not appropriate for drugs intended to treat this condition.  
 
13.  Risk-Benefit Considerations 
 
Assessment of risks and benefits involves an evaluation of the effect of the investigational drug 
on head lice infestation. The primary efficacy analysis should demonstrate a clinically 
meaningful and statistically significant result.  If present, toxicities related to the pharmacologic 
effects of the investigational drug (e.g., neurotoxicity) also should be considered as part of the 
overall risk-benefit assessment. 
 
C.  Other Considerations 
 
1.  Relevant Nonclinical Considerations 
 
It is recommended that in vitro studies be conducted using head lice and their eggs to investigate 
the mechanism of action and identify the active ingredient(s) of the drug.  Such studies should be 
designed to evaluate the mortality/hatchability of head lice/eggs treated with the drug. 
 
If the mechanism of action of the drug is related to the head louse nervous system, the potential 
for human neurotoxicity should be adequately addressed in nonclinical safety pharmacology and 
toxicology studies. Other safety concerns for topical pediculicide drugs that should be 
adequately addressed in nonclinical studies include, but are not limited to, dermal irritation, 
ocular irritation, dermal sensitization, and phototoxicity.  Dermal irritation can be evaluated in 
conjunction with repeat-dose dermal toxicity studies.  The in vivo rabbit ocular irritation test is 
not recommended for the evaluation of ocular irritation.  Ocular irritation can be evaluated by 
conduct of appropriate in vitro or ex vivo tests (e.g., the bovine corneal opacity and permeability 
assay). In vitro assays can be used as a screen for clinical assessment of dermal sensitization and 
phototoxicity. See ICH M3(R2) for additional information regarding the recommended 
nonclinical studies to support the proposed clinical dose and treatment regimen of the drug. 
 
2.  Labeling Considerations 
 
A representative indication statement for a topical drug intended to treat head lice infestation 
should be: 
 
11 
  Contains Nonbinding Recommendations 
[Drug X] is indicated for the topical treatment of head lice infestation in patients (age) and 
older  
 
The INDICATIONS AND USAGE section of labeling for drugs for the treatment of head lice 
infestation generally should also include information about adjunctive measures, such as: 
 
[Drug X] should be used in the context of an overall lice management program: 
 
	   Wash (in hot water) or dry-clean all recently worn clothing, hats, used bedding, and 
towels  
 
 	  Wash (in hot water) personal care items such as combs, brushes, and hair clips 
 
 	  Use a fine-tooth comb or special nit comb to remove nits and dead lice  
 
The risk of accidental ingestion should be discussed in the WARNINGS AND PRECAUTIONS 
and PATIENT COUNSELING INFORMATION sections.17  To prevent accidental ingestion, the 
discussion of the risk should include a recommendation to use the drug on pediatric patients only 
under direct adult supervision. 
 
Safety concerns, especially with respect to use in the pediatric age group (e.g., accidental 
ingestion, misapplication), generally support the inclusion of FDA-approved patient labeling 
(i.e., Patient Information).  For those drugs having complex application procedures, FDA-
approved Instructions for Use would be beneficial to enhance compliance.   
                                                 
17 See the guidances for industry Warnings and  Precautions, Contraindications, and Boxed  Warning Sections  of  
Labeling for Human Prescription Drug and  Biological Products  Content and Format and Patient Counseling 
Information  Section  of Labeling for Human  Prescription  Drug and Biological Products  Content and Format. 
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