Recurrent Herpes Labialis: Developing Drugs for Treatment and Prevention

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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

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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 Administration’s (FDA’s) 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, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
as recommendations, unless specific regulatory or statutory requirements are cited. The use of
the word should in Agency guidances means that something is suggested or recommended, but
not required.
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.

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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, Öberg,
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, Öberg, 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

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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.

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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 50 and EC90 values) for each isolate using a
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 50 ), and a therapeutic index (CC 50
value/EC 50 value) should be calculated. In general, the therapeutic index should be greater than
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

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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 50 values, and studies should include controls for cytotoxicity.
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 drug’s 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.

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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

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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.

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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.

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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

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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 3–4 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.

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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 FDA’s 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.

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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.

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‒ 	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

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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.

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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

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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.

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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 50 values or antiviral activity data from animals with similar
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.

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