Recurrent Herpes 
Labialis:  Developing 
Drugs for Treatment 
and Prevention 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
November 2017 
Clinical/Medical 
 
   
Recurrent Herpes 
Labialis:  Developing 
Drugs for Treatment 
and Prevention 
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/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services  
Food and Drug Administration  
Center for Drug Evaluation and Research (CDER)  
 
November 2017 
Clinical/Medical 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  DEVELOPMENT PROGRAM ....................................................................................... 3 
A.  General Drug Development Considerations ................................................................................3 
1. Pharmacology/Toxicology Considerations ......................................................................................3 
2. Virology Considerations ...................................................................................................................3 
a.  Mechanism of action .................................................................................................................4 
b.  Antiviral activity in cell culture .................................................................................................4 
c.  Cytotoxicity and mitochondrial toxicity ....................................................................................4 
d.  Combination antiviral activity ...................................................................................................5 
e.  Activity in animal models ..........................................................................................................5 
f.  Resistance and cross-resistance ..................................................................................................5 
3. Early Phase Clinical Considerations ...............................................................................................6 
a.  Investigational drugs ..................................................................................................................6 
b.  Previously approved drugs with a new formulation and/or route of administration .................6 
4. Relevant Nonclinical Safety Considerations ....................................................................................7 
B.  Phase 2 and Phase 3 Clinical Development ..................................................................................7 
1. Study Population ..............................................................................................................................7 
2. Efficacy Considerations ...................................................................................................................8 
a.  Treatment indication ..................................................................................................................8 
b.  Prevention indication .................................................................................................................8 
3. Safety Considerations .......................................................................................................................9 
4. Specific Efficacy Trial Considerations .............................................................................................9 
a.  Study design ..............................................................................................................................9 
b.  Study population ......................................................................................................................10 
c.  Inclusion and exclusion criteria ...............................................................................................10 
d.  Randomization, stratification, and blinding ............................................................................10 
e.  Specific populations ................................................................................................................11 
f.  Dose selection ..........................................................................................................................12 
g.  Choice of comparators .............................................................................................................12 
h.  Efficacy endpoints ...................................................................................................................12 
i.  Study procedures and timing of assessments ...........................................................................13 
j.  Endpoint adjudication ..............................................................................................................14 
k.  Statistical considerations .........................................................................................................14 
l.  Clinical virology considerations ...............................................................................................15 
m.  Accelerated approval (subpart H) considerations...................................................................16 
n.  Risk-benefit considerations .....................................................................................................16 
C.  Other Considerations ...................................................................................................................16 
1. Risk Management Considerations ..................................................................................................16 
2. Pharmacokinetic/Pharmacodynamic Considerations ....................................................................16 
REFERENCES ............................................................................................................................ 18 
  Contains Nonbinding Recommendations 
Recurrent Herpes Labialis:  
Developing Drugs for Treatment and Prevention 
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 office responsible for this guidance as listed on the 
title page.   
 
 
 
 
I.  INTRODUCTION  
 
The purpose of this guidance is to assist sponsors in the development of drugs for the treatment 
and prevention of recurrent herpes labialis (RHL).  Specifically, this guidance addresses the 
Food and Drug Administrations (FDAs) current thinking regarding the overall development 
program and clinical trial designs to support the development of drug products with an antiviral 
mechanism of action used to prevent and/or treat RHL caused by either herpes simplex virus 
type 1 or 2 (HSV-1 or HSV-2) in immunocompetent subjects.  This guidance does not address 
the development of drug products used to treat systemic, genital, or disseminated herpes virus 
infections or herpes labialis in immunosuppressed subjects.  
 
This guidance does not contain discussions 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.2 
 
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.  
 
 
                                                 
1 This guidance has been prepared by the Division of Antiviral Products in the Center for Drug Evaluation and 
Research at the Food and Drug Administration.  
 
2 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
Drugs guidance Web page at 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
1  Contains Nonbinding Recommendations 
II.  BACKGROUND 
 
Infections caused by viruses of the herpes virus family are increasingly frequent.  One of the 
more common forms of such infections is RHL, which is primarily caused by HSV-1 but also 
caused by HSV-2, which is more commonly associated with genital herpes (Harmenberg, Oberg, 
et al. 2010; Cunningham, Griffiths, et al. 2012).  In the United States from 2005 to 2010, the 
seroprevalence of HSV-1 was 53.9 percent, and the seroprevalence of HSV-2 was 15.7 percent 
(Bradley, Markowitz, et al. 2014).  It is estimated that 20 to 40 percent of adults in the U.S. 
population experience RHL (Bader, Crumpacker, et al. 1978; Lowhagen, Bonde, et al. 2002). 
 
The presentation of a primary herpes labialis episode in adults can vary from an asymptomatic 
presentation to an acute self-limiting gingivostomatitis often associated with posterior 
pharyngitis and tonsillitis (Arduino and Porter 2006).  Fever, malaise, headache, and sore throat 
are presenting features and can be associated with vesicles on the tonsils and the posterior 
pharynx.  These vesicles if present can rupture to form ulcerative lesions with grayish exudates.  
This type of primary infection that is associated with oral and labial lesions occurs in less than 10 
percent of patients.  Acute herpetic gingivostomatitis usually lasts 5 to 7 days, and the symptoms 
subside in 2 weeks.  The virus then establishes latency in the sensory ganglia, and when 
reactivated, virus particles travel along sensory neurons to the skin and other mucosal sites and 
cause RHL (Harmenberg, Oberg, et al. 2010).  A variety of stimuli can lead to reactivation, 
including exposure to ultraviolet light, fever, psychological stress, and menstruation.  These 
recurrent episodes can be associated with lesions or asymptomatic viral shedding.  When 
symptomatic, the episodes can be painful and disfiguring.  
 
The outer edge of the vermilion border is the most common site of reactivation; on average three 
to five lesions are present.  Episodes typically progress through sequential phases, including a 
prodromal stage followed by stages characterized by papules, or pustules (vesicles), and/or 
ulcers.  The prodromal stage, comprised of sensory symptoms occurring in the absence of 
cutaneous lesions, generally resolves in 4 to 5 days.   
 
Approximately 25 to 50 percent of RHL episodes do not progress beyond the prodromal or 
papule stage; these are referred to as aborted lesions (Spruance, Overall, et al. 1977).  In the 
immunocompetent host, episodes that progress beyond the prodromal stage are self-limited and 
generally heal spontaneously within 8 to 10 days.  
 
Herpes labialis recurrences are diagnosed primarily on the basis of clinical presentation.  
Diagnostic testing for HSV-1 or HSV-2, while available, is not used routinely in the clinical 
setting.  Diagnostic confirmation, if needed, can be provided by isolation of HSV in tissue 
culture, indirect immunofluorescent staining of skin scrapings with monoclonal antibodies, or 
polymerase chain reaction.  
 
The FDA has approved a number of prescription topical and systemic drugs for the treatment of 
RHL.  For antiviral drugs, the goal of therapy is to block viral replication in order to shorten the 
duration of symptoms and accelerate the healing of lesions leading to a return to normal skin.  
Because episodes of RHL are self-limited with an expected duration of 5 to 10 days, if treatment 
is either warranted or requested, it should be initiated as soon as possible to ensure an optimal 
2  Contains Nonbinding Recommendations 
and beneficial therapeutic effect.  To date, the FDA has not approved an antiviral drug for the 
prevention of RHL. 
 
 
III.  DEVELOPMENT PROGRAM 
 
General considerations pertinent to nonclinical development and early clinical development are 
outlined in this section.  Sponsors can also obtain regulatory advice early in the development 
program, before submitting an investigational new drug application (IND), through the pre-IND 
consultation program.3  
 
A.  General Drug Development Considerations 
 
1.  Pharmacology/Toxicology Considerations 
 
Pharmacology/toxicology development for HSV antivirals should follow existing guidances for 
nonclinical drug development with regard to study requirements, study duration, timing, and 
local tolerance, as well as fixed-drug combinations.4 
 
If it is anticipated that a subject may be exposed to an HSV antiviral for prevention of 
recurrences, or for 26 weeks or longer (cumulative dosing over a calendar year), chronic toxicity 
and carcinogenicity studies are generally needed to support chronic dosing in subjects. 
 
If existing data do not support trials in subjects, nonclinical studies to support a change in the 
route of administration (e.g., oral to topical) or reformulation of an already approved drug 
substance may be needed.5  Similarly, if systemic absorption following a change in the route of 
administration is higher than previously observed, additional pharmacology/toxicology studies 
may be needed.  Sponsors can discuss the need for such studies with the Division of Antiviral 
Products (DAVP). 
 
2.  Virology Considerations 
 
Nonclinical virology studies can facilitate dose selection and study design to provide proof of 
concept and data supporting an antiviral claim.  Additional recommendations for general 
antiviral drug development can be found in the guidance for industry Antiviral Product 
Development  Conducting and Submitting Virology Studies to the Agency. 
 
                                                 
3 See the FDA Web page Getting Started With the Division of Antiviral Products Pre-IND Process at 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplicat
ions/InvestigationalNewDrugINDApplication/Overview/ucm077546.htm.  
 
4 See the ICH guidance for industry M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials 
and Marketing Authorization for Pharmaceuticals. 
 
5 See the guidance for industry and review staff Nonclinical Safety Evaluation of Reformulated Drug Products and 
Products Intended for Administration by an Alternate Route.   
3  Contains Nonbinding Recommendations 
a.  Mechanism of action 
 
The mechanism by which an anti-HSV investigational drug specifically inhibits HSV-1 and/or 
HSV-2 replication or a virus-specific function should be investigated using cell culture, 
biochemical, structural, and/or genetic studies that include evaluation of the effect of the drug on 
relevant stages of the virus life cycle.  Mechanism-of-action studies should include appropriate 
controls for assessing the specificity of anti-HSV activity, which may include assessments of 
activity against HSV-1 and/or HSV-2 proteins that are targeted by the investigational drug, 
relevant host proteins, and other viruses. 
 
b.  Antiviral activity in cell culture 
 
HSV-1 and HSV-2 are closely related but distinct viruses, and both cause RHL.  The antiviral 
activity of oral, parenteral, and topical drugs should be characterized in cell culture to assess the 
anti-HSV-1 and/or anti-HSV-2 activity and to identify a target plasma concentration for the 
evaluation of oral- or parenteral-administered drug products in HSV-infected subjects.  Anti-
HSV activity studies should include assessments against several geographically and temporally 
distinct isolates of HSV-1 and HSV-2 (20 or more of each); the vast majority of which should be 
U.S. isolates.  Sponsors should obtain additional isolates from relevant countries if non-U.S. sites 
will be used in clinical studies.  Sponsors should determine the effective concentration at which 
virus replication is inhibited by 50 and 90 percent (EC  and EC  values) for each isolate using a 
50 90
quantitative assay.  Sponsors should consider and discuss with the DAVP the merits of 
developing an investigational drug showing significantly greater activity for HSV-2 compared to 
HSV-1 given the relative proportions of each in the infected population in the United States. 
 
c.  Cytotoxicity and mitochondrial toxicity 
 
The cytotoxic effects of the drug should be quantified directly in the cells used for assessing anti-
HSV activity, and a 50 percent cytotoxic concentration (CC ), and a therapeutic index (CC  
50 50
value/EC  value) should be calculated.  In general, the therapeutic index should be greater than 
50
10.  Cytotoxicity should also be assessed using various cell lines and primary cells cultured 
under proliferating conditions for several cell divisions and nonproliferating conditions.  
Deoxynucleoside/deoxynucleotide analog inhibitors have been associated with bone marrow 
precursor cell toxicity, and therefore, sponsors should assess inhibitors for toxicity with 
appropriate controls. 
 
Mitochondrial toxicity for all drugs should be evaluated in a glucose-containing medium and a 
galactose-containing medium (Marroquin, Hynes, et al. 2007).  Sponsors should evaluate 
mitochondrial toxicity assessments with drug exposures for several cell divisions.  Whenever 
possible, positive controls for mitochondrial toxicity studies should be relevant to the class of the 
investigational drug.  The active triphosphate of nucleoside analog inhibitors also should be 
evaluated in biochemical assays with mitochondrial DNA and RNA polymerases (Arnold, 
Sharma, et al. 2012).   
 
Sponsors should perform these biochemical and cell-based assessments for potential cellular and 
mitochondrial toxicity as a complement to in vivo toxicology assessments and not in lieu of in 
4  Contains Nonbinding Recommendations 
vivo studies.  Sponsors should interpret the results from these studies in the context of the in vivo 
toxicology, nonclinical, and clinical pharmacokinetic data to help assess clinical risk. 
 
d.  Combination antiviral activity 
 
Early in development, combination antiviral activity relationships of the investigational drug and 
approved drugs for HSV should be characterized in cell culture to identify any combinations 
where the antiviral activity is antagonistic if the sponsor anticipates any future combination 
therapy (e.g., fixed dose combinations, add-on use, co-administration).  Each component of a 
combination drug that will contain at least one novel drug substance should be assessed for 
antagonism between the components.6  For all combination antiviral activity assessments, 
sponsors should provide combination index values or synergy scores when the two drugs are 
combined at their individual EC  values, and studies should include controls for cytotoxicity.  
50
Before testing combinations of the drugs in coinfected subjects, combination antiviral activity 
relationships for nucleos(t)ide and deoxynucleos(t)ide HSV investigational drugs for which there 
will be systemic exposure should also be assessed with approved drugs for hepatitis B virus, 
hepatitis C virus, and human immunodeficiency virus-1 (HIV-1), as appropriate. 
 
e.  Activity in animal models 
 
Demonstration of HSV-1 and HSV-2 antiviral activity in an animal model is not needed for drug 
approval.  However, if such studies are conducted and provided in support of an HSV therapy 
program, we recommend including the HSV type, time course plots of viral load data for each 
animal, and an assessment of resistance development. 
 
f.  Resistance and cross-resistance 
 
Amino acid substitutions associated with the development of resistance to the investigational 
drug can be identified by genotyping the target gene, and the conferred fold shift in susceptibility 
can be determined using appropriate cell culture assays.  Sponsors can use the results from these 
studies to:  (1) identify resistance pathways; (2) validate resistance assays for use in clinical 
trials; (3) determine whether the genetic barrier for resistance development is high or low; (4) 
predict whether the genetic barrier for resistance may vary as a function of concentration of the 
investigational drug; (5) assess the potential for cross-resistance with other anti-HSV drugs, 
particularly acyclovir; and (6) support the drugs hypothesized mechanism of action.  Resistant 
viruses selected in cell culture provide important controls for phenotypic assessment of clinical 
isolates. 
 
Resistance studies can include evaluation of the potential for cross-resistance, both to approved 
drugs and to drugs in development when possible, particularly focusing on those in the same 
drug class and other classes targeting the same protein or protein complex.  The antiviral activity 
of the investigational drug can be assessed against mutant viruses that are resistant to drugs 
within the same drug class as the investigational drug as well as assessed against a representative 
sample of viruses resistant to other approved anti-HSV drugs. 
                                                 
6 See the guidance for industry Antiviral Product Development  Conducting and Submitting Virology Studies to 
the Agency.  
5  Contains Nonbinding Recommendations 
 
Deoxynucleoside analogs for the treatment of herpes viruses have been found to have antiviral 
activity against HIV-1 and can select for resistant variants (Tachedjian, Hooker, et al. 1995; 
McMahon, Siliciano, et al. 2008; Lisco, Vanpouille, et al. 2008).  Sponsors of such drugs for 
HSV should determine the cell culture antiviral activity of the active moiety against HIV-1.  If 
the drug demonstrates antiviral activity, sponsors should determine genotypically and 
phenotypically the development of resistance to the investigational drug by selecting resistant 
HIV-1 variants.  Resistance studies should include evaluation of cross-resistance to approved 
nucleo(t)side reverse transcriptase inhibitors for HIV-1. 
 
3.  Early Phase Clinical Considerations 
 
The extent of this development phase depends on whether the treatment under study is a new 
molecular entity or a previously approved drug seeking a new indication with or without a new 
route of administration or a new formulation.  In all cases, the DAVP will consult with the 
Division of Dermatology and Dental Products to assess the need for dermatologic safety studies 
for drugs being developed for topical administration. 
 
a.  Investigational drugs  
 
The development program for orally or topically administered investigational drugs should 
include standard phase 1 safety studies as specified in the guidance for industry, investigators, 
and reviewers Exploratory IND Studies.  Following phase 1, the FDA strongly advises sponsors 
to progress to proof-of-concept and dose-ranging phase 2 trials to establish a sufficiently well-
tolerated and active dose for phase 3 trials.  The phase 2 trials can be of similar design to phase 3 
trials, albeit smaller.  The primary objective should be a reduction in the duration of the episode 
of RHL by at least 1/2 day.  The number of phase 2 trials needed to proceed to phase 3 clinical 
development depends on the treatment under study and the safety and efficacy results observed 
in at least one such trial. 
 
Of note, a phase 2 dose-response trial is one type of adequate and well-controlled trial that, if 
measuring appropriate endpoints in appropriate populations, can contribute to substantial 
evidence of effectiveness (21 CFR 314.126).  In addition, dose- or exposure-response analyses 
within trials can provide additional support for approval of different doses or dosing regimens. 
 
b.  Previously approved drugs with a new formulation and/or route of 
administration  
 
Sponsors should discuss with the FDA early clinical development programs for previously 
approved drugs with new formulations and/or routes of administration.  A drug previously 
approved for oral administration and now being developed for a new indication and/or dosage 
likely will not need an extensive phase 1 development program.  However, as discussed 
previously, an oral drug product being developed as a topical drug product may need to undergo 
6  Contains Nonbinding Recommendations 
dermatologic safety testing.  A proof-of-concept phase 2 clinical trial may be needed depending 
on the formulation, route of administration, and dose under study.  
 
4.  Relevant Nonclinical Safety Considerations 
 
In general, the nonclinical toxicology studies for drugs active against RHL are anticipated to be 
similar to studies for other antimicrobial drugs.  One question that can be asked is whether 
animal toxicology data to support chronic administration are needed.  Although RHL treatment is 
usually for 5 to 10 days, sponsors should consider the possibility of multiple courses of treatment 
or long-term prevention in determining the nature and duration of nonclinical safety studies.   
 
For instance, if the indication for a drug is treatment of RHL, long-term carcinogenicity studies 
in rodents usually are not needed.  If, on the other hand, the drug is indicated for the prevention 
of RHL, carcinogenicity studies in rats and mice as well as 6-month toxicology studies in a 
rodent and a nonrodent species should be conducted before approval.  Longer duration studies 
may be needed when the duration of lifetime exposures to drugs used frequently in an 
intermittent manner in the treatment and prevention of chronic or recurrent conditions generally 
exceeds 6 months.  The ICH guidance for industry S1A The Need for Long-Term Rodent 
Carcinogenicity Studies of Pharmaceuticals provides detailed information concerning the 
conditions under which the sponsor should conduct carcinogenicity studies.  The sponsor should 
also refer to the ICH guidance for industry M3(R2) Nonclinical Safety Studies for the Conduct of 
Human Clinical Trials and Marketing Authorization for Pharmaceuticals when designing its 
studies. 
 
B.  Phase 2 and Phase 3 Clinical Development 
 
1.  Study Population 
 
The study populations should include immunocompetent adults or adolescents at risk for 
developing recurrent episodes of herpes labialis, defined as individuals experiencing at least four 
recurrent episodes per year.  Enrollment of a population that has experienced multiple 
recurrences is preferred for the treatment indication to allow early initiation of treatment at the 
first symptoms or signs of recurrence.  For a prevention indication, the enrollment of a 
population with a greater likelihood of recurrence is critical to demonstrate a preventive effect.  
It may be possible to enroll children 12 years of age or younger (6 to 12 years of age) depending 
on the formulation under development and its safety profile (i.e., a drug product for topical use) 
in either the adult trials or in separate concurrently run trials.  Sponsors are advised to discuss 
this possibility with the FDA.   
 
Given estimates of disease prevalence in the United States, we recommend sponsors obtain 
adequate representation of U.S. subjects within the application to support approval.  If trials are 
conducted outside the United States, the FDA strongly encourages sponsors to refer to the 
recommendations outlined in the guidance for industry Acceptance of Foreign Clinical Studies 
 
and the requirements in 21 CFR 312.120. 
 
7  Contains Nonbinding Recommendations 
2.  Efficacy Considerations  
 
For investigational drugs, the FDA strongly encourages sponsors to conduct two adequate and 
well-controlled phase 3 trials (superiority) to support the intended indication.  However, a single 
persuasive and clinically meaningful study for each indication (treatment and prevention) 
submitted together may provide substantial evidence of effectiveness sufficient for approval of 
both indications.  In circumstances where a drug previously approved for RHL treatment is being 
developed for the prevention indication, a single superiority study may be considered to provide 
substantial evidence of effectiveness for the intended indication.  In addition if the FDA 
previously approved a drug for a disease caused by HSV-1 or HSV-2 and that drug is now being 
developed for RHL, one adequate and well-controlled trial may suffice.  For a prevention-only 
indication, the FDA strongly recommends data from two phase 3 trials.  See section III.B.4., 
Specific Efficacy Trial Considerations, for details.  Sponsors should also refer to the guidance for 
industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products.   
 
a.  Treatment indication 
 
In general, sponsors should design treatment trials to demonstrate a decrease in the duration of 
episode (DOE) of RHL by at least 1/2 day relative to a control.  Spontaneous resolution of RHL 
can occur in 5 to 10 days, and approved antiviral drugs that reduce the duration of RHL episodes 
by at least 1/2 day are considered clinically beneficial.  Sponsors can consider secondary 
endpoints, such as a reduction in the number of ulcerative lesions, pain reduction, or an increase 
in the number of aborted lesions for labeling claims; however, discussion with the FDA and 
agreement before designing pivotal trials is strongly encouraged. 
 
b.  Prevention indication 
 
Prevention of RHL denotes no recurrences or less-frequent recurrent episodes in at-risk 
individuals.  Currently, the FDA has not approved a drug for the prevention of RHL; therefore, a 
trial for this indication should be a placebo-controlled superiority trial.  
 
While designing a prevention trial or trials, sponsors should consider the duration of observation 
(the FDA strongly recommends 12 months) and the determination of the primary endpoint.  An 
appropriate primary endpoint for prevention studies is either the number of confirmed 
recurrences observed in subjects on suppressive therapy over a 12-month period or the time to 
first recurrence, defined as the time from randomization until the onset of an episode of RHL.   
 
Drugs in development for the treatment and/or prevention of RHL in immunocompetent hosts 
are not eligible for consideration under 21 CFR part 312, subpart E, Drugs Intended to Treat 
Life-Threatening and Severely-Debilitating Illnesses, breakthrough therapy designation, fast 
track, or priority review because of the non-life-threatening and self-limited nature of the 
disease.  
 
8  Contains Nonbinding Recommendations 
3.  Safety Considerations  
 
Generally, the FDA advises sponsors to discuss the size of an appropriate safety database for 
their drug products at the end-of-phase 2 meetings.  Sponsors should also consider the route of 
administration in determining the size of the safety database for either the treatment or the 
prevention indication.  The safety database can include both adult and pediatric subjects. 
 
For topical treatments, the safety database may need topical safety studies.  Sponsors should 
discuss with the DAVP the need for such studies.   
 
Sponsors should also discuss with the DAVP the number of subjects that should be studied to 
have an acceptable safety database for a new previously unapproved drug product that will be 
used chronically for a prevention indication.  We anticipate that a minimum of 1,000 subjects 
treated with the proposed dose for oral drugs or topicals with systemic absorption will be studied.  
However, a topical drug with no systemic absorption may have a safety database between 500 
and 1,000 subjects.  
 
4.  Specific Efficacy Trial Considerations 
 
a.  Study design 
 
Study designs appropriate for the study of the treatment or prevention of RHL can be found 
below: 
 
  Treatment trials 
 
Applications for a treatment indication of RHL should include double-blind, placebo-
controlled trials that focus on early treatment intervention by prospectively dispensing the 
investigational drug (or placebo) for subject-initiated treatment at the first sign or 
symptom of a recurrent episode.  Given the self-limited nature of RHL, the FDA 
considers such placebo-controlled superiority trials to be the most direct route to 
providing evidence of efficacy.  In addition to placebo-controlled trials, sponsors could 
also consider superiority trials against an active control (i.e., an approved antiviral drug 
for RHL). 
 
A single-arm, open-label trial design is not considered appropriate for a treatment 
indication.  Noninferiority trials have not been considered feasible for an RHL treatment 
indication because of the modest and variable treatment effects observed to date with 
available treatments (1/2 day difference in the DOE endpoint).  Expected outcomes 
cannot be predicted well enough to support an adequate noninferiority margin. 
 
  Prevention trials 
 
Currently, the FDA has not approved a drug for the prevention of RHL; therefore, a trial 
for this indication should be a placebo-controlled superiority trial.  Similar to trials 
9  Contains Nonbinding Recommendations 
designed for a treatment indication, the FDA does not consider a single-arm, open-label 
trial design to be an appropriate alternative for evaluating prevention of RHL. 
 
b.  Study population 
 
As mentioned above, RHL affects a substantial percentage of the U.S. population.  Phase 3 trials 
should focus on RHL in healthy immunocompetent adults and adolescents.  See section 
III.B.4.e., Specific populations, for discussion of pediatric and adolescent patients. 
 
c.  Inclusion and exclusion criteria  
 
Generally, trials assessing the treatment (or prevention) of RHL should be conducted in a 
population of subjects who have had multiple recurrences and are experienced with their disease 
course.  This enables subjects to rapidly identify recurrences and to self-initiate treatment as soon 
as possible during the prodrome phase.  The inclusion criteria should specify:  
 
  Experienced subjects with a history of at least 34 episodes of RHL in the previous 12-
month period should be enrolled 
 
  At least half of the episodes should be vesicular in nature   
 
  At least half of the episodes should be preceded by prodromal symptoms 
 
  Only immunocompetent subjects should be enrolled 
 
Note:  Culture or serologic documentation is not needed for the RHL indication.  The diagnosis 
is clinical and based on previous history of recurrences.  However, HSV-1 and HSV-2 could 
respond differently to an investigational drug product, which could affect efficacy results (for 
further discussion, see section III.B.4.l., Clinical virology considerations). 
 
Sponsors should exclude subjects who are receiving any ongoing treatment active against HSV.  
This includes both nonprescription and prescription medications.  
 
Also sponsors should exclude subjects who have evidence of active malignancy or 
immunodeficiency disease, require chronic use of immunosuppressive drugs (e.g., systemic 
steroids) or topical steroids, or chronically use antiviral medication with activity against HSV.  
Sponsors should also exclude subjects who cannot be reliably expected to comprehend or 
satisfactorily assess a herpetic lesion, who have abnormal skin conditions (e.g., acne, eczema, 
rosacea, psoriasis, albinism, chronic vesiculo-bullous disorders) that occur in the area ordinarily 
affected by RHL, or who have had a vaccine for HSV-1 (typically oral herpes) or HSV-2 
(typically genital herpes). 
 
d.  Randomization, stratification, and blinding 
 
Sponsors should conduct double-blind trials, given the subjectivity of a number of the endpoints, 
such as time to pain resolution or symptom improvement. 
10  Contains Nonbinding Recommendations 
 
e.  Specific populations 
 
Specific populations in which RHL can be studied are listed below: 
 
  Pediatrics 
 
Decisions regarding pediatric development may vary depending on various issues 
including, but not limited to, formulation and safety profile.  Therefore, the FDA 
encourages sponsors to begin discussions about their pediatric formulations and clinical 
development plans early because the FDA requires sponsors to submit pediatric study 
plans under the Pediatric Research Equity Act (PREA).7  The following discussion is 
based on situations where the antiviral drug is expected to act similarly in adults and 
pediatric patients.  Sponsors should discuss with the FDA other situations on a case-by-
case basis. 
 
Because the course and pathophysiology of RHL is similar in adults and pediatric 
patients (6 to 17 years of age), and the effect of the antiviral drug product is expected to 
be the same in adults and children, extrapolation of efficacy from adults to children is 
generally acceptable.  In this situation, pharmacokinetic (if systemically absorbed) and 
safety studies may be considered adequate to extend the indications to these pediatric age 
groups. 
 
The annual prevalence of RHL in children from 8 to 11 years of age has been estimated 
to be 12 percent in some studies.  The annual prevalence of RHL in adolescents between 
12 and 17 years of age has been estimated to be 17 percent in some studies.  Therefore, 
studies in the pediatric population are required under PREA.8  Generally, herpes labialis 
in children younger than 6 years of age is a primary infection and not recurrent in nature 
(Rioboo-Crespo Mdel, Planells-del Pozo, et al. 2005; Arduino and Porter 2008).  
Therefore, the FDA generally will grant a partial waiver from PREA study requirements 
in patients younger than 6 years of age.  Pediatric studies should evaluate patients 6 to 17 
years of age as described below:   
 
  Antiviral drugs with favorable risk-benefit assessments should be evaluated in 
pediatric patients 6 to 11 years of age.  A minimum of 50 pediatric patients (6 to 11 
years of age) should be studied to adequately characterize dosing and safety of the 
drug product.   
 
  Antiviral drugs with favorable risk-benefit assessments should be evaluated in 
adolescent subjects 12 to 17 years of age.  A minimum of 50 adolescent subjects (12 
                                                 
7 See PREA (Public Law 108-155; section 505B(e)(2)(A) of the Federal Food, Drug, and Cosmetic Act (FD&C 
Act); 21 U.S.C. 355B) as amended by the Food and Drug Administration Safety and Innovation Act (FDASIA) 
(Public Law 112-144).  See also the draft guidance for industry Pediatric Study Plans:  Content of and Process for 
Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans.  When final, this guidance will 
represent the FDAs current thinking on this topic. 
 
8 See PREA (section 505B(e)(2)(A) of the FD&C Act; 21 U.S.C. 355B) as amended by FDASIA.  
11  Contains Nonbinding Recommendations 
to 17 years of age) should be studied to adequately characterize dosing and safety of 
the drug product.    
 
  Other specific populations 
 
Sponsors should discuss with the DAVP the determination of the efficacy and safety of 
the treatment under study in other specific populations.  The route of administration and 
the degree of systemic absorption for a topical drug product will be factors in determining 
the need for further assessment.   
 
f.  Dose selection 
 
Animal studies and human dose-ranging trials can contribute to dose selection for phase 3 
clinical trials.  Sponsors can use exposure-response relationships to help guide dose selection.  
Sponsors should explore various pharmacodynamic parameters, such as those relating to viral 
clearance and healing time.  As previously noted, sponsors should conduct adequate phase 2 
trials before designing the phase 3 trials.  
 
For some drugs, more than one route of administration can be considered.  Different dosing, 
safety, and efficacy issues may arise with different routes of administration.  For example, 
certain drugs may be available for both oral and topical use and appropriate dosing should be 
established for both routes. 
 
g.  Choice of comparators  
 
RHL is a self-limited disease.  Therefore, a placebo comparator arm is considered ethical and 
most appropriate in a superiority trial design for either the treatment or the prevention indication.  
Other approved treatments for RHL also can be used as comparators in a superiority trial for the 
treatment indication.   
 
h.  Efficacy endpoints 
 
Efficacy endpoints for both treatment and prevention indications are discussed below: 
 
  For the treatment indication 
 
The DOE endpoint provides the most accurate assessment of the effectiveness of RHL 
treatments to date because it measures the effect of the treatment under study on the full 
spectrum of the RHL episode (i.e., all stages of lesion evolution). 
 
DOE is defined as the time from treatment initiation to the healing of primary lesions 
(loss of crust) for subjects who experienced a vesicular lesion.  For subjects whose 
primary lesions were not vesicular in nature, DOE is the time from the treatment 
initiation to the return to normal skin or to the cessation of symptoms, whichever occurs 
last. 
 
12  Contains Nonbinding Recommendations 
  For the DOE endpoint, the protocol should provide: 
 
  Frequency for assessing the acute episodes  
 
  Daily investigator follow-up during the acute episodes until complete healing has 
occurred 
 
  Subject diary in which a subject can record the lesion status at least twice daily so 
that time of assessment and lesion or disease status can be accurately documented 
 
  For the DOE endpoint, the mean and median values should be provided.  A study 
evaluating the treatment of RHL should show clinically meaningful and statistically 
significant results to make a claim of decreased episode duration.  The DAVP 
considers a difference in DOE of at least 1/2 day (mean and median) between 
treatment arms is clinically meaningful. 
 
  Secondary endpoints can include: 
 
  Investigator-assessed prevention of progression to a classical lesion (aborted 
lesions) 
 
  Subject-assessed duration of lesion pain 
 
  Subject-assessed severity of lesion pain 
 
  Incidence of recurrence and time to recurrence following treatment  
 
For labeling claims based on secondary endpoints, the results should be 
clinically meaningful and statistically significant. 
 
Note:  For incidence of recurrence, sponsors should continue to follow all enrolled 
subjects for the prespecified time period and should define a priori the follow-up 
population. 
 
  For the prevention indication 
 
For the primary endpoint, the FDA recommends either the number of confirmed 
recurrences observed in subjects on suppressive therapy over a 12-month period or the 
time to first recurrence defined as the time from randomization until the onset of an 
episode of RHL.  It should be stressed for this indication that the duration of observation 
is paramount.  Shorter observation periods, such as 6 months, may be inadequate to 
collect an appropriate amount of clinically meaningful events. 
 
i.  Study procedures and timing of assessments 
 
13  Contains Nonbinding Recommendations 
Sponsors should provide enrolled and randomized subjects with study treatment and directions to 
start treatment as soon as possible after the appearance of their prodromal symptoms.  
 
For the treatment indication, subjects should be assessed by the investigator within 12 to 24 
hours of the start of the prodromal symptoms and treatment initiation (self-initiation) and then 
observed daily thereafter (or as often as possible) by the investigator or subinvestigator until the 
primary vesicular lesion heals or, for those subjects without a vesicular lesion, skin returns to 
normal.  In addition, sponsors should provide subjects with subject diaries in which they should 
record, at a minimum of twice daily, their symptoms such as pain, tenderness, tingling, itching, 
and discomfort and the stage of their herpes lesions (e.g., normal lip, erythema, papule, vesicle, 
ulcer, crust) to help the investigators in their overall assessment of healing.  
 
For the prevention indication, subjects should be assessed within 24 to 48 hours of the 
development of prodromal symptoms or an active lesion.  Sponsors should consider the 
treatment of such subjects.  One option is to continue the drug under study and to assess the DOE 
as well as other secondary endpoints.  At the time of protocol development, sponsors should 
discuss with the DAVP the treatment of subjects who develop a recurrence.  
 
j.  Endpoint adjudication 
 
Generally, the drug development of RHL treatment has been straightforward with a well-defined 
primary endpoint, and adjudication is not considered feasible because the endpoint is a subjective 
assessment based on investigator and patient observations, and it would be difficult to have an 
adjudication committee to add further specificity.  The same is expected for the prevention 
indication. 
 
k.  Statistical considerations 
 
Before the trial initiation, sponsors should provide a protocol with a detailed SAP stating the trial 
hypotheses and the analysis methods.  
 
  Treatment studies  
 
The primary endpoint in RHL treatment studies in adults should be the decrease in DOE.  
As compared to time to healing in patients who develop typical vesicular lesions, DOE 
allows one to evaluate the effect of the intervention in everyone who initiates treatment at 
onset of symptoms and takes into account aborted lesions.  The primary efficacy analysis 
should be based on the differences in the time to healing or return to normal skin of all 
lesions among groups, and appropriate statistical methods for event-time data should be 
employed.  Sponsors should assess both the mean and median DOE.  Minimizing missing 
data is paramount, and sponsors should have explicit plans to handle missing data.  
Sponsors should include a priori a strategy in the SAP to control the overall type I error 
rate for any secondary endpoints that may form the basis of labeling claims.  Sponsors 
should refer to the draft guidance for industry Multiple Endpoints in Clinical Trials. 
 
14  Contains Nonbinding Recommendations 
The primary efficacy analysis, as well as the safety analyses, should be performed on all 
randomized subjects who initiated treatment (received at least one dose of treatment) for 
their first recurrence episode after randomization.  It should be noted that because the 
DOE is the primary efficacy endpoint, sponsors should assess all subjects with RHL who 
initiated treatment and not only those subjects who develop vesicular lesions.  
 
  Prevention studies 
 
In prevention studies, the primary endpoint should be either the number of confirmed 
recurrences observed in subjects on suppressive therapy over a 12-month period or the 
time to first recurrence defined as the time from randomization until the onset of an 
episode of RHL.  However, as noted in section III.B.2.b, Prevention indication, the FDA 
strongly recommends that the number of recurrences over a 12-month period be 
provided. 
 
Minimizing missing data is important, and investigators should be diligent in obtaining 
the final status of subjects either on or off the assigned treatment and either in the study 
or, if terminated, not in the study.  The primary analysis should be performed on all 
randomized subjects who initiated treatment.  Sponsors should perform appropriate 
sensitivity analyses to assess the robustness of the results to the strategy for handling 
missing data including subjects who would discontinue or drop out. 
 
l.  Clinical virology considerations 
 
HSV-1 and HSV-2 have distinct viral proteins and may exhibit differential responses to an 
investigational drug, which could affect efficacy results in clinical trials if the drug is only 
effective against one type of HSV and the clinical study population was infected with both types.  
Therefore, to determine if the investigational drug exhibits antiviral activity against both HSV 
types, sponsors may want to consider determining the type of HSV infection present at baseline.  
The assay used to genotype the HSV type in enrolled subjects should be included with the 
clinical trial protocol, and the performance characteristics of the assay should be provided.  
However, the diagnosis of RHL is clinical; therefore, the FDA does not consider virologic 
confirmatory studies mandatory. 
 
In general, the HSV-1 or HSV-2 present in recurrent lesions is not likely to persist at the site of 
the lesion in a latent state; therefore, resistance analysis of a virus from immunocompetent 
subjects is considered optional.  Sponsors may want to consider performing a resistance analysis 
in a subset of subjects who failed treatment (i.e., failure of lesions to heal) to determine if 
baseline or emergent substitutions that occur in the targeted genome region correlate with 
resistance.  
 
For resistance analyses, any changes, including mixtures, in the amino acid sequence of the 
target protein present in on-treatment or follow-up samples, but not in the baseline sample, can 
be reported as having developed during therapy.  In addition, sponsors should analyze baseline 
samples to identify HSV genetic polymorphisms that are associated with differential antiviral 
15  Contains Nonbinding Recommendations 
activity against the investigational drug.  Sponsors should consult the DAVP for the most current 
format for submission of resistance data.  
 
For virologic assessments in clinical trials, the FDA recommends the use of FDA-cleared assays, 
when available, and a central laboratory.9  Sponsors can collect results from local lab tests, 
identifying the assay or assays used.  If investigational assays are used, sponsors should provide 
performance characteristics with geographically and temporally distinct isolates.  
 
m.  Accelerated approval (subpart H) considerations 
 
Because RHL is not considered a serious or life-threatening disease, the regulations in 21 CFR 
part 314, subpart H, have not been used for approval of antivirals used to treat RHL and are 
unlikely to be appropriate in most instances.  
 
n.  Risk-benefit considerations 
 
The overall risk-benefit assessment should be considered in the context of disease, which in this 
case is a nonserious and self-limited condition.  RHL in immunocompetent individuals is also 
not associated with life-threatening complications, and several approved antivirals are available 
for treatment.  For the treatment indication, clinically meaningful benefits should outweigh 
toxicity risks.  As discussed previously, demonstrating large efficacy improvements over 
currently approved drugs is challenging.  A favorable safety and tolerability profile is critical for 
the target population.  In addition, other advantages over the current standard of care, such as 
shorter duration of dosing or convenient administration resulting in improved adherence, are 
considerations in the overall assessment.  
 
Likewise for the prevention indication, a favorable drug safety profile is critical because the 
target population consists of immunocompetent individuals with a relatively benign recurrent 
condition.  For a chronic suppressive drug, safety with cumulative or chronic dosing should be 
emphasized.  Because there are no approved drugs for prevention of RHL, the overall assessment 
should rely on the level of clinical benefit the drug offers in reducing the frequency of 
recurrences or increasing the recurrence-free periods. 
 
C.  Other Considerations 
 
1.  Risk Management Considerations 
 
Given the self-limited nature of RHL, in general the FDA does not consider risk minimization 
strategies necessary.  
 
2.  Pharmacokinetic/Pharmacodynamic Considerations 
 
Various administration routes have been considered for RHL drugs:  oral, topical, and buccal.  
For oral administration, plasma drug concentrations are presumed to be correlated with 
                                                 
9 See the FDA web page 510(k) Premarket Notification at 
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/pmn.cfm.  
16  Contains Nonbinding Recommendations 
concentrations at the site of action although prediction of clinical effect cannot be assumed.  
However, for topical and buccal administration, drug concentrations at the dermal layer of the 
skin may better correlate with the antiviral activity.  Generally, comparing concentrations in a 
targeted organ to cell culture EC  values or antiviral activity data from animals with similar 
50
concentrations in a targeted organ may help select doses for initial clinical trials.10 
 
Sponsors can use clinical endpoints as response metrics in the exposure-response evaluations.  
For prevention trials, sponsors should use the clinical endpoint.  Relationships between each of 
these assessments and the principal efficacy endpoints should be assessed based on all available 
data.  
 
Sponsors should explore any drug exposure-related toxicity to assess the relationship between 
drug concentration and the adverse event, to identify the highest tolerable dose, and to determine 
the probability of an adverse event with a given drug exposure.  This information can also guide 
dose adjustments for specific populations and drug interactions. 
 
 
                                                 
10 The FDA encourages sponsors to consult the FDA when considering a nonanimal testing method believed to be 
suitable, adequate, validated, and feasible. The FDA will consider if the alternative method could be assessed for 
equivalency to an animal test method. 
17  Contains Nonbinding Recommendations 
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