Human Immunodeficiency 
Virus-1 Infection:  Developing 
Systemic Drug Products for 
Pre-Exposure Prophylaxis 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
March 2019 
Clinical/Antimicrobial 
   
Human Immunodeficiency 
Virus-1 Infection:  Developing 
Systemic Drug Products for 
Pre-Exposure Prophylaxis 
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) 
 
March 2019 
Clinical/Antimicrobial
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  DEVELOPMENT CONSIDERATIONS ........................................................................ 2 
A.  Nonclinical Considerations ........................................................................................................... 2 
B.  Clinical Pharmacology and Clinical Considerations for Long-Acting Systemic Drug 
Products ................................................................................................................................................... 3 
C.  Dose Selection ................................................................................................................................. 3 
D.  Systemic Drug Product Characteristics That Affect End-User Acceptability ......................... 4 
III.  PHASE 3 CLINICAL TRIAL DESIGN FEATURES  KEY CONSIDERATIONS 4 
A.  Enrollment Criteria ....................................................................................................................... 4 
B.  Trial Design .................................................................................................................................... 4 
C.  Efficacy Endpoint .......................................................................................................................... 5 
D.  Other Trial Features ...................................................................................................................... 5 
E.  Specific Population Considerations .............................................................................................. 6 
1. Pregnant Women .............................................................................................................................. 6 
2. Adolescents ...................................................................................................................................... 7 
  Contains Nonbinding Recommendations 
 
Human Immunodeficiency Virus-1 Infection:  Developing Systemic 
Drug Products for Pre-Exposure Prophylaxis 
Guidance for Industry1 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the 
title page. 
 
 
 
I.  INTRODUCTION  
 
The purpose of this guidance is to provide to sponsors nonclinical and clinical recommendations 
specific to the development of systemic drug products, with a focus on long-acting systemic drug 
products (including small molecules and monoclonal antibodies), regulated within the Center for 
Drug Evaluation and Research at the Food and Drug Administration (FDA) for the prevention of 
sexually acquired human immunodeficiency virus-1 (HIV-1) infection.  Specifically, this 
guidance addresses FDAs current thinking regarding the overall development program and 
clinical trial designs to support the development of systemic drug products for the prevention of 
HIV-1 infection.  Investigational drug products for further development as pre-exposure 
prophylaxis (PrEP) can include the following:  (1) an oral drug product approved for the 
treatment of HIV-1 infection that is subsequently developed as oral PrEP, (2) an oral drug 
product approved for the treatment of HIV-1 infection that is reformulated as a long-acting drug 
product or other delivery system (e.g., injectable, implantable device) for PrEP, or (3) a new 
investigational systemic drug product that is developed for treatment and/or prevention of HIV-1 
infection. 
 
This guidance does not address the development of vaginal microbicide drug products.  That 
topic is discussed in the guidance for industry Vaginal Microbicides:  Development for the 
Prevention of HIV Infection (November 2014) (vaginal microbicides guidance). 2  The following 
additional information can be found in the vaginal microbicides guidance:  detailed nonclinical 
development, including in vitro virologic studies, specific information related to topical use and 
trials in female subjects, and more detailed information relating to protocol data collection and 
procedures.  Except for the assessment of local microbicide effects, which are unique to vaginal 
microbicide development, the vaginal microbicides guidance is also generally applicable to the 
development of systemic drug products.  
                                                 
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 
guidance web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 
1  Contains Nonbinding Recommendations 
 
 
This guidance also does not discuss 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 (September 1998) and E10 Choice of Control Group and Related Issues in 
Clinical Trials (May 2001), respectively.  
 
FDA recognizes the challenges in evaluating systemic drug products for the prevention of 
sexually acquired HIV-1 infection.  FDA continues to evaluate possible approaches for the 
development of new therapies for HIV prevention and will update this guidance if new 
information becomes available. 
 
FDA encourages the sponsor considering development of systemic drug products for the 
prevention of HIV-1 infection to communicate with FDA through the preinvestigational new 
drug application consultation program.3 
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required.  
 
 
II.  DEVELOPMENT CONSIDERATIONS 
 
A.  Nonclinical Considerations 
 
Nonclinical virology considerations presented in the guidance for industry Human 
Immunodeficiency Virus-1 Infection:  Developing Antiretroviral Drugs for Treatment (November 
2015) are applicable to the development of systemic drug products for HIV-1 prophylaxis and 
should be reviewed.  
 
Depending on the mechanism of action of some systemic drug products for HIV-1 prophylaxis, 
the sponsor should consider the potential of a drug to enhance HIV infectivity.  For example, the 
sponsor should evaluate monoclonal antibodies for potential antibody-dependent enhancement of 
infection. 
 
The sponsor can use animal models of HIV-1 infection (e.g., macaque/simian HIV rectal 
challenge models) to further support clinical development of systemic drug products (e.g., by 
determining threshold drug concentrations at which infection occurs to aid in initial dose 
selection or by exploring potentially effective drug combinations, delivery formulations, and 
dosing regimens).4 
                                                 
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 We support the principles of the 3Rs (reduce/refine/replace) for animal use in testing when feasible.  FDA 
encourages sponsors to consult with review divisions when considering a nonanimal testing method believed to be 
 
2  Contains Nonbinding Recommendations 
 
 
B.  Clinical Pharmacology and Clinical Considerations for Long-Acting 
Systemic Drug Products 
 
The sponsor can use an oral lead-in period (using an immediate-release formulation), if 
available, to achieve and maintain desired targeted drug concentrations and/or address early 
safety concerns before administering a long-acting systemic drug product.  If an adverse reaction 
occurs during the lead-in period, an oral formulation allows for immediate withdrawal of an 
investigational systemic drug product, which is typically not feasible after a long-acting 
formulation has been dosed.  
 
Long-acting systemic drug products can be developed in the absence of an immediate-release 
systemic drug product depending on the drug characteristics, including the known in vitro and in 
vivo safety profile of the systemic drug product and the potential for removal if formulated in an 
implantable device.  For some drugs, an immediate release systemic drug product may not be 
feasible (e.g., monoclonal antibodies) or necessary (e.g., solid implant releasing systemic drug 
product with a short half-life).  
 
In cases for which desired targeted drug concentrations are not expected to be reached for a 
considerable time period, the sponsor can consider other dosing strategies, such as the use of a 
loading dose (larger than the maintenance dose) or other maintenance dosing regimens. 
 
Early in development, evaluation of the complete systemic concentration time course of the drug 
after the last administered dose is critical to assess the impact of residual drug concentrations on 
drug safety, development of resistance, and potential for continued drug interactions after 
stopping PrEP.  In phase 1 multiple-dose studies, the sponsor should fully characterize the 
complete systemic concentration time course and collect blood samples for the measurement of 
drug concentration (pharmacokinetic (PK) samples) until the drug concentration is no longer 
detectable in plasma. 
  
C.  Dose Selection 
 
The sponsor should use model-informed drug development approaches that leverage the 
available information (nonclinical and clinical) across the development program to inform dose 
selection whenever possible. 
 
The sponsor should generally target systemic drug product exposures consistent with those of 
HIV-1 treatment (if available).  
 
The sponsor can also select a dose or doses that result in exposures that are similar to or several 
fold higher than animal exposures that showed protection (if studies using animal models were 
conducted) if acceptable safety margins exist.  Exposures below a known human HIV-1 
treatment dose (if previously studied for treatment), but similar to animal model exposures that 
showed protection, may be acceptable for phase 2 and phase 3 clinical trials. 
                                                 
suitable, adequate, validated, and feasible.  FDA will consider if the alternative method could be assessed for 
equivalency to an animal test method. 
3  Contains Nonbinding Recommendations 
 
 
In the absence of supportive clinical data or nonhuman primate data that showed protection, the 
sponsor may target systemic drug product exposures that are anticipated to exhibit antiviral 
activity (e.g., several fold above the cell culture protein-binding-adjusted EC  value of the active 
90
moiety) if acceptable nonclinical safety margins exist. 
 
D.  Systemic Drug Product Characteristics That Affect End-User Acceptability 
 
The effectiveness of any intervention for HIV-1 prevention is strongly correlated with user 
adherence.  Therefore, subject adherence and subject retention in clinical trials are critical to the 
overall evaluation of safety and efficacy of an investigational systemic drug product.  A systemic 
drug product with less frequent and more convenient dosing may be associated with greater 
adherence.  Early in development, the sponsor should focus on systemic drug product 
characteristics (e.g., the number, frequency, and volume of injections; duration and 
characteristics of an implant) that might affect end-user adherence.  The Division of Antiviral 
Products (DAVP) strongly encourages pretrial feasibility assessments to understand user 
preferences and to ensure systemic drug product attributes do not adversely affect subject 
adherence to a study regimen. 
 
Data obtained in early development can guide systemic drug product reformulation, if needed, to 
optimize user acceptability before large-scale trials are started.   
 
 
III.  PHASE 3 CLINICAL TRIAL DESIGN FEATURES  KEY CONSIDERATIONS 
 
A.  Enrollment Criteria 
 
The trial population should include healthy, non-HIV-infected sexually active adult men and 
women at substantial risk of acquiring HIV.  Confirmation of HIV infection status before trial 
entry is critical, preferably by use of a diagnostic test that is sensitive to acute infection (e.g., 
capable of detecting HIV-1 RNA). 
 
B.  Trial Design  
 
The sponsor should ensure that HIV prevention trials are randomized, double-blind, placebo-
controlled trials or active-controlled superiority or noninferiority (NI) trials.5  The sponsor 
should consider trial designs for the following populations: 
 
  Trials in men who have sex with men.  Trials should use an active control and can be 
either superiority trials or NI trials.  The NI margin is determined using historical 
evidence of the treatment effect of an active control based on adequate and well-
controlled superiority trials.  Assumptions based on historical data, however, may be 
influenced by prior levels of adherence.  The sponsor should consider these assumptions 
when estimating the HIV infection rate in subjects receiving an active control that is 
                                                 
5 For trials in other high-risk adult populations (e.g., serodiscordant couples), the sponsor should discuss trial 
designs with DAVP. 
4  Contains Nonbinding Recommendations 
 
based on historical data and should discuss the assumptions with DAVP prior to trial 
initiation.  (Likewise, lack of treatment adherence or dropouts can affect the 
interpretation of prospective trial findings.) 
 
  Trials in high-risk women.  FDA recommends superiority designs because 
determination of an NI margin is difficult or impossible in this population because of the 
variable historical evidence of HIV prevention efficacy in at-risk women. 
 
In general, two adequate and well-controlled trials are often needed to provide substantial 
evidence of effectiveness.  However, the sponsor can consider evidence based on a single phase 
3 trial acceptable if the results are robust with internal consistency, clinically and statistically 
persuasive, and supported by additional evidence (e.g., if the systemic drug product is already 
demonstrated to be effective for HIV treatment).  If the sponsor is considering using a single-trial 
approach, the sponsor should discuss this with DAVP. 
 
C.  Efficacy Endpoint 
 
The primary endpoint is the HIV infection rate per 100 person-years and is analyzed based on the 
intent-to-treat population, including all randomized subjects.  The sponsor should not exclude 
subjects based on factors impacted by postrandomization selection. 
 
The sponsor should follow all enrolled subjects for a minimum of 12 months and until the last 
enrolled subject completes the trial and the majority of subjects have received 24 months of 
follow-up.   
 
D.  Other Trial Features 
 
The sponsor should submit for review a plan to assess adherence as part of the protocol and 
statistical analysis plan, and the sponsor should ensure that the plan includes objective methods, 
such as plasma drug levels, to provide estimates of drug product use over time.  The sponsor 
should specify methods to document information on known factors that affect HIV transmission, 
such as condom usage and use of other prevention modalities.  However, the sponsor should not 
adjust the primary analysis for actual use or compliance. 
 
The Agency recommends the use of an FDA-approved HIV-1 RNA assay, when available, and 
the assay used should be specified in the clinical trial protocol.  If the baseline/screening test 
does not use an HIV-1 RNA-specific assay or assays sensitive for acute infections, the sponsor 
should store baseline samples for retrospective HIV-1 RNA analysis (e.g., by RT-PCR) for all 
subjects.  The sponsor should not consider retrospectively identified HIV-infected subjects 
missed by the screening assay prophylaxis failures and can exclude these subjects from the 
primary efficacy analysis.   
 
Long-acting systemic drug products may persist for extended periods after systemic drug product 
discontinuation, potentially at concentrations too low for effective prophylaxis but high enough 
to select drug-resistant virus in case of acute infection.  The sponsor should consider providing 
oral drugs for prophylaxis (e.g., emtricitabine/tenofovir DF) to subjects who discontinue a 
5  Contains Nonbinding Recommendations 
 
systemic drug product with a long half-life and who are uninfected at the time of systemic drug 
product cessation but who remain at risk of HIV-1 infection.  The sponsor should continue oral 
prophylaxis coverage until the investigational systemic drug product has been cleared.  If oral 
prophylaxis coverage is deemed necessary, the sponsor should include these considerations in 
proposed labeling.  
 
The sponsor should obtain PK samples from all subjects at trial visits at which HIV testing is 
performed and archive the samples for future analysis.  The sponsor should record the time of 
previous doses and the time of sample collection for all PK samples.  The sponsor should also 
analyze PK samples for subjects who seroconvert and compare the PK samples to those of a 
matched seronegative cohort.   
 
The sponsor can use drug or drug metabolite concentration data to examine systemic drug 
product adherence.   
 
Depending on the systemic drug product characteristics (e.g., if there is a device component for 
self-administration), the sponsor may need human factor and label comprehension studies to 
ensure labeling instructions for use are appropriate for the U.S. population.  See the draft 
guidance for industry and FDA staff Human Factor Studies and Related Clinical Study 
Considerations in Combination Product Design and Development (February 2016).6 
 
E.  Specific Population Considerations 
 
1.  Pregnant Women7 
 
Women who become pregnant during premarketing trials may be able to continue dosing; FDAs 
decision on a sponsors proposal to dose pregnant women is made on a case-by-case basis and is 
dependent on the available data.8   
 
Before considering including pregnant women in clinical trials, the sponsor should provide the 
following data.  Findings from the toxicology studies should support the benefit-risk assessment 
to continue dosing in pregnant women. 
 
  Completed reproductive toxicology studies, including data from fertility and early 
embryonic development studies, embryo-fetal development studies, and pre- and 
postnatal development studies 
 
  Completed genotoxicity studies 
 
                                                 
6 When final, this guidance will represent the FDAs current thinking on this topic. 
 
7 See the draft guidance for industry Pregnant Women: Scientific and Ethical Considerations for Inclusion in 
Clinical Trials (April 2018).  When final, this guidance will represent the FDAs current thinking on this topic. 
 
8 See section III. A. 5. c., Safety in specific populations, of the vaginal microbicides guidance for more specific 
details on the types of data to be collected for women who become pregnant and continue dosing in clinical trials. 
6  Contains Nonbinding Recommendations 
 
  Toxicity studies in two species to support the duration of exposure in human trials 
 
2.  Adolescents 
 
The vaginal microbicides guidance outlines a two-stage approach for development of 
microbicides for use in adolescents, consisting of the collection of initial safety data from 
subjects 16 to 18 years old, followed by the recruitment of adolescents younger than 16 years old 
(depending on the clinical needs and pediatric research requirements of participating study sites).  
A two-stage approach may be appropriate for microbicide development given the potential 
differences in vaginal epithelial inflammation/toxicity and absorption within adolescent age 
groups.  For systemic drug product development, the preferred approach for adolescents is 
enrollment in the adult clinical trials, or for the sponsor to conduct an adolescent study in parallel 
with the adult trials.  The sponsor should make every effort to submit data from adolescents with 
the new drug application submission. 
 
Extrapolation of efficacy from adults to adolescents is acceptable for systemic HIV drug 
products because acquisition of HIV infection in adolescents and the effects of systemic drug 
products are sufficiently similar between adult and adolescent populations.  Therefore, after 
critical PK parameters for a systemic HIV drug product are identified from adult data, the 
adolescent development program can rely on matching the relevant adolescent and adult 
exposure parameters to demonstrate efficacy in the adolescent population.  The sponsor should 
submit additional data to support safety in adolescents and to assess adherence. 
 
The sponsor should collect supportive safety data in adolescents, unless the safety profile of the 
systemic drug product is already established in pediatrics.   
 
Adherence data are important because lack of adherence could undermine the efficacy and safety 
of a systemic drug product in adolescents.  Collection of usage data in adolescents is desirable 
until adolescent adherence is better understood for a given prevention modality (e.g., oral pill, 
injection).  Once DAVP has reviewed usage and adherence information for a given prevention 
modality, the sponsor should discuss with DAVP the utility of the existing data to support use of 
a similar prevention modality (e.g., second oral systemic drug product seeking approval) and 
whether additional usage data are needed (e.g., if the dosing regimen differs). 
7