Respiratory Syncytial Virus 
Infection:  Developing 
Antiviral Drugs for 
Prophylaxis and Treatment 
Guidance for Industry 
 
 
 
 
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to https://www.regulations.gov.  Submit written 
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061, Rockville, MD  20852.  All comments should be identified with the 
docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact Jeff Murray, MD, MPH, at 301-796-1500.  
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
October 2017 
Clinical/Antimicrobial 
17072dft.docx 
10/06/17   
Respiratory Syncytial Virus 
Infection:  Developing 
Antiviral Drugs for 
Prophylaxis and Treatment 
Guidance for Industry 
 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
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) 
 
October 2017 
Clinical/Antimicrobial 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  DEVELOPMENT PROGRAM ....................................................................................... 3 
A.  General Drug Development Considerations ................................................................................3 
1. Nonclinical Virology Development Considerations .........................................................................4 
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 
2. General Considerations for Phase 1 and Phase 2 Development .....................................................5 
a.  Phase 1a/First-in-human trials ...................................................................................................6 
b.  Phase 2 trials ..............................................................................................................................6 
c.  Data needed to proceed to phase 3 ............................................................................................9 
3. Dose Selection ..................................................................................................................................9 
4. Drug Development Population .........................................................................................................9 
5. Efficacy Considerations .................................................................................................................10 
6. Safety Considerations .....................................................................................................................10 
B.  Phase 3 Efficacy Trial Considerations ........................................................................................11 
1. Trial Design ....................................................................................................................................11 
a.  Treatment of RSV LRTI ..........................................................................................................11 
b.  Prophylaxis for severe RSV LRTI ..........................................................................................12 
2. Trial Population .............................................................................................................................12 
3. Entry Criteria .................................................................................................................................12 
4. Randomization, Stratification, and Blinding ..................................................................................13 
5. Other Populations ..........................................................................................................................13 
6. Use of Active Comparators ............................................................................................................14 
7. Efficacy Endpoints ..........................................................................................................................14 
a.  Treatment .................................................................................................................................14 
b.  Prophylaxis ..............................................................................................................................16 
8. Trial Procedures and Timing of Assessments ................................................................................16 
9. Statistical Considerations ...............................................................................................................17 
10.  Accelerated Approval (Subpart H) Considerations ...................................................................17 
11.  Risk-Benefit Considerations ......................................................................................................18 
C.  Other Considerations ...................................................................................................................18 
1. Relevant Nonclinical Safety Considerations ..................................................................................18 
2. PK/PD Considerations ...................................................................................................................19 
a.  PK measurement ......................................................................................................................19 
b.  PD measurement ......................................................................................................................19 
c.  Modeling considerations ..........................................................................................................20 
3. Clinical Virology Considerations ...................................................................................................20 
a.  RSV diagnostic assays for screening and events .....................................................................20 
b.  Resistance analysis ..................................................................................................................20 
4. Regulatory Considerations .............................................................................................................21 
i 
   
REFERENCES ............................................................................................................................ 22 
 
 
ii 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Respiratory Syncytial Virus Infection:   
2  Developing Antiviral Drugs for Prophylaxis and Treatment  
1
3  Guidance for Industry  
4   
5   
6   
7  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
8  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
9  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
10  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
11  for this guidance as listed on the title page.   
12   
13   
14   
15  I.  INTRODUCTION  
16   
17  The purpose of this guidance is to assist sponsors in the clinical development of drugs for the 
18  treatment and prevention of disease caused by respiratory syncytial virus (RSV) infection.2  
19  Specifically, this guidance addresses the Food and Drug Administrations (FDAs) current 
20  thinking regarding the overall development program and clinical trial designs for the 
21  development of drugs and biological products that support an indication for treatment and 
22  prevention of disease caused by RSV infection.  This draft guidance is intended to serve as a 
23  focus for continued discussions among the Division of Antiviral Products (DAVP), 
24  pharmaceutical sponsors, the academic community, and the public.3  This guidance focuses 
25  primarily on the development of drugs with antiviral mechanism for RSV-related illness in 
26  infants and young children (e.g., bronchiolitis) but also briefly discusses development for other 
27  populations.  The sections of this guidance that discuss nonclinical development are intended to 
28  provide guidance regarding drug development for both prophylaxis and treatment.  
29   
30  This guidance does not address development of drugs that target the host response to RSV 
31  infection, vaccines, or blood-derived products.  This guidance does not contain discussion of the 
32  general issues of statistical analysis or clinical trial design.  Those topics are addressed in the 
                                                 
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 For the purposes of this guidance, all references to drugs include both human drugs and therapeutic biological 
products unless otherwise specified. 
 
3 In addition to consulting guidances, sponsors are encouraged to contact the division to discuss specific issues that 
arise during the development of drugs for treatment and prevention of disease caused by RSV infection.  
 
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33  ICH guidances for industry E9 Statistical Principles for Clinical Trials and E10 Choice of 
34  Control Group and Related Issues in Clinical Trials, respectively.4  
35   
36  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
37  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
38  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
39  the word should in Agency guidances means that something is suggested or recommended, but 
40  not required.  
41   
42   
43  II.  BACKGROUND 
44   
45  RSV has two subtypes, RSV A and RSV B, that may circulate concurrently, and both have been 
46  associated with disease.  RSV infections range from asymptomatic to severe and life-threatening 
47  lower respiratory tract infection (LRTI).  LRTI in infants and young children most commonly 
48  presents as bronchiolitis, which is characterized by increased mucus production, bronchospasm, 
49  and acute inflammation, edema, and necrosis of epithelial cells lining small airways 
50  (Viswanathan, King, et al. 2003).  Other manifestations of LRTI in all age groups include 
51  pneumonia, as well as exacerbations of chronic lung disease such as asthma and chronic 
52  obstructive pulmonary disease.  All types of RSV LRTI are associated with a spectrum of illness 
53  ranging from mild cough and wheezing to fulminant respiratory failure.  Populations at high risk 
54  for more severe disease include term infants younger than 6 months of age, preterm infants, older 
55  adults, patients with chronic lung or cardiac disease, and immunocompromised patients, 
56  particularly those who have undergone hematopoietic stem cell transplantation (HSCT).  
57   
58  Currently, there are no established definitions for disease severity in pediatric patients with RSV 
59  bronchiolitis.  Therefore, the following definitions are used for the purpose of this guidance.  
60  Severe RSV bronchiolitis is characterized by signs and symptoms of LRTI (e.g., tachypnea, 
61  nasal flaring, and hypoxemia) with obvious respiratory distress, accompanied by poor feeding.  
62  Moderate RSV bronchiolitis is defined as symptomatic respiratory illness without overt 
63  respiratory distress, which often requires additional caregiver activities (e.g., frequent nasal 
64  suctioning, repositioning, changes to feeding schedule) to sustain normal daily activities.  
65  Moderate disease is more likely to result in a visit to a health care provider than mild disease, 
66  which is defined as symptomatic respiratory illness with limited disruption of daily activities 
67  (e.g., feeding, sleeping). 
68   
69  One challenge in the development of drugs for treatment and prophylaxis of RSV disease in 
70  pediatric patients is a lack of full understanding of the pathogenesis of RSV infection.  The role 
71  of RSV cytotoxicity versus that of the host immune response in RSV disease remains uncertain.  
72  Therefore, optimal approaches for treatment and prophylaxis of RSV disease have not been 
73  established. 
74   
                                                 
4 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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75  Currently, two drugs are FDA approved for prevention or treatment of RSV LRTI in pediatric 
76  patients:  palivizumab for prophylaxis and aerosolized ribavirin for treatment.  In 1996, 
77  palivizumab (a monoclonal antibody that targets the RSV F protein) was approved for the 
78  following indication:   
79   
80  prevention of serious lower respiratory tract disease caused by RSV in children at high risk 
81  of RSV disease.   
82   
83  Palivizumab was initially approval based on the results of a double-blind placebo controlled 
84  study of 1,502 patients 24 months of age or younger with bronchopulmonary dysplasia (BPD) or 
85  infants with premature birth (35 weeks or less gestation) who were 6 months of age or younger at 
86  study entry.  In this study, reductions of RSV hospitalization were observed for both of these 
87  high-risk groups.  Among patients with BPD, 7.9% (39/496) of palivizumab patients were 
88  hospitalized compared to 12.8% (34/266) of placebo patients.  Among premature infants without 
89  BPD, 1.8% (19/234) of palivizumab-treated pediatric patients were hospitalized compared to 
90  8.1% (9/506) of pediatric patients who received placebo.  The use of palivizumab in the United 
91  States is largely guided by a clinical practice guideline published by the American Academy of 
92  Pediatrics (AAP) in 2014 and the AAPs 2014 guidance for palivizumab prophylaxis (Ralston, 
93  Lieberthal, et al. 2014; AAP Committee on Infectious Diseases and Bronchiolitis Guidelines 
94  Committee 2014).  In 1985, FDA approved aerosolized ribavirin for treatment of hospitalized 
95  infants and young children with severe LRTIs caused by RSV.  The approval was based on two 
96  small placebo-controlled studies in nonmechanically ventilated infants; the results of which were 
97  subsequently published (Hall, McBride, et al. 1983; Taber, Knight, et al. 1983).  On day 3 of 
98  treatment, both studies showed statistically significant differences in mean symptom scores.  
99  However, a subsequent meta-analysis by Randolph and Wang (1996) cited many methodological 
100  errors in the studies that had supported aerosolized ribavirins clinical benefits, and the authors 
101  concluded that treatment with aerosolized ribavirin failed to impart any clinically significant 
102  benefits.  At present, health care providers perceptions of limited clinical benefits, in addition to 
103  concerns for mutagenicity, carcinogenicity, and teratogenicity with ribavirin, has resulted in 
104  infrequent use of ribavirin for the treatment of RSV-associated illness.  Currently, ribavirin is 
105  used mainly when the outcome of an RSV LRTI could be fatal, such as in RSV infections in 
106  bone marrow transplant patients. 
107   
108   
109  III.  DEVELOPMENT PROGRAM 
110   
111  A.  General Drug Development Considerations 
112   
113  Sponsors considering development of antiviral drugs for the treatment of RSV infection are 
114  encouraged to communicate with FDA through the pre-Investigational New Drug application 
115  (pre-IND) consultation program.5  Pre-IND consultation with FDA is optional; although, it may 
116  be particularly helpful for sponsors with limited experience in the IND process or to obtain FDA 
                                                 
5 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.  
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117  advice in the development of drug products with unique considerations based on mechanistic 
118  action or novel treatment approaches or the use of novel biomarkers. 
119   
120  The following sections address nonclinical virology, phase 1 and 2 trials, target population, and 
121  overall efficacy and safety considerations.  
122   
123  1.  Nonclinical Virology Development Considerations 
124   
125  The antiviral activity of an investigational drug should be determined using a cell culture model 
126  of infection before submission of an initial investigational new drug application (IND).  
127  Additional recommendations for antiviral drug development can be found in the guidance for 
128  industry Antiviral Product Development  Conducting and Submitting Virology Studies to the 
129  Agency. 
130   
131  a.  Mechanism of Action 
132   
133  Ideally, sponsors should determine the mechanism by which a drug inhibits RSV.  Mechanism of 
134  action investigations should include an assessment of the drugs specificity for the target and 
135  should employ appropriate controls, such as uninfected cells, cells infected with viruses other 
136  than RSV, and/or cells infected with drug-resistant RSV variants.  Biochemical or subcellular 
137  quantitative assays supporting the mechanism of action should report the 50 and 90 percent 
138  inhibitory concentrations (IC  and IC  values).   
50 90
139   
140  b.  Antiviral activity in cell culture 
141   
142  The antiviral activity of a new drug should be characterized using a cell culture model of RSV 
143  infection to demonstrate activity and identify a target concentration for the initial clinical trials.  
144  Antiviral activity studies should include assessments against a broad range of RSV A and RSV B 
145  laboratory and clinical isolates, preferably representing multiple RSV seasons and different 
146  geographic regions.  The effective concentrations at which virus replication is inhibited by 50 
147  and 90 percent (EC and EC  values) should be determined using a quantitative assay.  Also, 
50  90
148  the sponsor should determine the effect of serum and mucosal proteins on antiviral activity and 
149  calculate a protein binding-adjusted EC  value.  Sponsors developing monoclonal antibodies 
50
150  should evaluate the potential for antibody dependent enhancement of infection.  
151   
152  c.  Cytotoxicity and mitochondrial toxicity 
153   
154  The cytotoxicity evaluation should make use of the same cells and culture conditions (e.g., drug 
155  exposure durations) used for determining antiviral activity.  A 50 percent cytotoxic concentration 
156  (CC ) and a therapeutic index (i.e., CC /EC ) should be calculated.  Sponsors may need to use 
50 50 50
157  different assay methodologies to evaluate cytotoxicity (Smee, Hurst, et al. 2017) and should note 
158  that cytotoxic effects that reduce viral replication may not manifest as cell death.  Therefore, 
159  assessments of cellular metabolism (e.g., transcription levels of cellular genes) may provide 
160  more relevant measures of toxicity.  The cytotoxicity evaluation should use multiple RSV-
161  susceptible human cell lines and primary cells cultured under proliferating and nonproliferating 
162  conditions.  Some investigational drugs (e.g., nucleos(t)ide analog inhibitors) should also be 
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163  evaluated for inhibitory activity against host DNA polymerases, mitochondrial DNA 
164  polymerases, and RNA polymerases, as well as for mitochondrial toxicity (Marroquin, Hynes, et 
165  al. 2007; Arnold, Sharma, et al. 2012).  Sponsors should note that these biochemical and cell-
166  based toxicity evaluations should not be considered substitutes for animal toxicity studies.  
167   
168  d.  Combination antiviral activity 
169   
170  The combination antiviral activity of approved drugs, such as approved anti-RSV drugs, that are 
171  likely to be used with an investigational drug should be evaluated early in drug development.  
172  Combination antiviral activity determinations with other investigational drugs should be 
173  conducted if the drugs may be used together in future trials or clinical practice.  The combination 
174  antiviral activity assessments should include concentrations spanning each drugs EC  value, 
50
175  when applicable, or relevant in vivo concentration.  These studies should also include 
176  combination cytotoxicity assessments.  
177   
178  e.  Activity in animal models 
179   
180  Demonstrating anti-RSV activity using animal models of infection could be useful for 
181  characterizing potential clinical use (e.g., prophylaxis or treatment, identifying the potential 
182  therapeutic window) and for providing additional proof-of-concept data to support clinical 
183  development.  Sponsors can discuss with the DAVP the selection and use of animal models of 
184  RSV infection before conducting studies.   
185   
186  f.  Resistance and cross-resistance 
187   
188  Resistance studies are useful for identifying resistance pathways, determining genetic barriers to 
189  resistance, assessing cross-resistance with other antiviral drugs, and providing additional data to 
190  support the proposed mechanism of action.  RSV variants that are resistant to an investigational 
191  drug should be selected using a cell culture or animal model of infection and then genotypically 
192  and phenotypically characterized.  The effect of each selected amino acid substitution on 
193  antiviral activity should be assessed individually and in combination using an RSV reverse 
194  genetics system when feasible.  
195   
196  Resistance studies should include an evaluation of potential cross-resistance with approved 
197  drugs.  In addition, cross-resistance between investigational drugs should be completed for drug 
198  combinations that may be used in clinical trials.  The evaluation should include:  (1) assessments 
199  of the antiviral activity of the investigational drug against mutant viruses that are resistant to 
200  other drugs and (2) assessments of the antiviral activities of other drugs against mutant viruses 
201  that are resistant to the investigational drug.  Evaluating cross-resistance is particularly important 
202  for drugs belonging to the same class (e.g., nucleoside analog inhibitors) or targeting the same 
203  viral protein or protein complex (e.g., fusion protein).  
204   
205  2.  General Considerations for Phase 1 and Phase 2 Development 
206   
207  The primary objective of early clinical trials should be to establish pharmacokinetics, safety, and 
208  antiviral activity and to provide sufficient data for study design and dose selection for phase 3 
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209  trials.  For most viral infections, efficacy of an antiviral drug is evaluated initially in adults and 
210  extrapolated to the pediatric population if the pathophysiology of the disease is similar in adults 
211  and pediatric patients.  Then, generally, pharmacokinetics, safety, and antiviral activity of the 
212  drug are evaluated in a smaller pediatric study.  However, the pathophysiology of RSV disease is 
213  thought to differ significantly between adult and pediatric patients.  One of the key physiological 
214  and anatomical differences between the respiratory tracts of infants and older children or adults 
215  is that infants have smaller airways, which appear to be more susceptible to compromise from 
216  inflammation caused by RSV infection.  Therefore, extrapolation of efficacy data from adults to 
217  pediatric patients is not possible for bronchiolitis and may not be possible for other types of RSV 
218  LRTI in young children.  Thus, sponsors should conduct fully powered clinical studies 
219  evaluating efficacy and safety of an antiviral drug for treatment of RSV infection in pediatric 
220  patients.  
221   
222  Before initiating pediatric studies, safety should be demonstrated in adult clinical trials and in 
223  juvenile animal toxicology studies, as discussed in section III.C.1., Relevant Nonclinical Safety 
224  Considerations.  In addition, transition to pediatric studies depends on adequate demonstration of 
225  proof of concept because, for any clinical investigation involving more than minimal risk, a 
226  potential benefit for pediatric patients must exist (21 CFR 50.52).  The types of trials to be 
227  considered may differ for treatment and prophylaxis indications.  In some cases, studies 
228  demonstrating in vivo antiviral activity in well-characterized animal model or models of RSV 
229  infection can also support initiation of pediatric clinical studies.   
230   
231  The following subsections provide general recommendations and examples for potential phase 1 
232  and phase 2 trial designs for investigational drugs for RSV disease treatment or prophylaxis. 
233   
234  a.  Phase 1a/First-in-human trials 
235   
236  Phase 1 trials should be conducted to assess safety and pharmacokinetics of the investigational 
237  drug.  In general, FDA recommends single- and/or multiple-ascending-dose trials in healthy 
238  adult subjects to assess safety and pharmacokinetics for the first-in-human trials.  Combined with 
239  nonclinical virology data, these trials support dose selection for phase 2 trials. 
240   
241  b.  Phase 2 trials 
242   
243  The primary objectives of phase 2 trials should be characterization of the safety profile and 
244  demonstration of proof of concept in adults and children.  Phase 2 trials should also identify the 
245  optimal dose and treatment duration of the investigational drug with regard to pharmacokinetics, 
246  safety, and antiviral activity.  Below are three potential study designs for phase 2 trials in adults 
247  and in children: 
248   
249  (1) Phase 2 RSV treatment trials in adults.  Currently, it is not known whether demonstration 
250  of antiviral (anti-RSV) activity in adults predicts efficacy in treatment of RSV LRTI in 
251  infants and young children.  However, obtaining evidence for proof of concept in adults 
252  with symptomatic RSV infection supports the prospect of clinical benefit in infants and 
253  young children.  Therefore, FDA recommends evaluating both antiviral activity (using 
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254  virological measurements) and clinical signs and symptoms in adults in early phase trials.  
255  Possible trial design options for proof-of-concept clinical trials include: 
256   
257  a.  Randomized, double-blind, placebo-controlled treatment trials in healthy adults 
258  experimentally infected with an acceptable RSV challenge strain.  Subjects who are 
259  experimentally inoculated should have established infections before receiving the 
260  investigational drug.  Many endpoints could be explored such as changes in RSV 
261  viral load, RSV-specific sign and symptom assessment scores, and mucus or tissue 
262  weights. 
263   
264  b.  Randomized, double-blind, comparative treatment trials of immunocompromised 
265  and/or elderly adults with acute symptomatic RSV infection.  Patients should have 
266  established infections before receiving the investigational drug.  Many endpoints 
267  could be explored in phase 2 trials, such as changes in RSV viral load, changes in 
268  clinical symptom scores, duration of hospitalization, and other indicators of disease 
269  progression or resolution.  A superiority trial comparing an investigational drug to 
270  ribavirin or an add-on superiority trial compared to a placebo added to a background 
271  of ribavirin could be considered for adult patients at institutions where ribavirin is 
272  considered part of the standard of care for acute RSV disease (e.g., 
273  immunosuppressed patients).  Placebo-controlled trials may be appropriate for 
274  patients for whom no approved therapy exists and for whom ribavirin is not 
275  considered standard of care.  
276   
277  Each of these trial designs has advantages and disadvantages.  Although challenge trials 
278  are simpler to conduct, demonstrating clinical benefit may be more difficult because 
279  disease is mild and generally limited to the upper respiratory tract.  Therefore, these trials 
280  may only be useful to demonstrate antiviral activity.  Randomized controlled trials of 
281  naturally infected patients are logistically more complicated than challenge trials; the 
282  former are more likely to enroll patients with clinically significant illness and lower 
283  respiratory tract disease and are therefore more likely to be able to demonstrate a clinical 
284  treatment benefit.  Ultimately, data from both types of trials may be used together to 
285  support further development for adult and pediatric indications. 
286   
287  (2) Phase 2 RSV prophylaxis trials in adults.  Historically, development of prophylactic 
288  drugs for RSV disease focused on passive immunoprophylaxis, defined as the prevention 
289  of disease by the administration of antibodies.  The scientific basis for 
290  immunoprophylaxis of RSV disease is based on observational studies of RSV infection in 
291  infants, which revealed a correlation between circulating maternal anti-RSV antibody 
292  levels and decreased severity of disease (Englund 1994).  Development of new drugs for 
293  RSV prophylaxis may need proof-of-concept trials in adults before pediatric studies.  
294  Examples of proof-of-concept trials in adults include the following: 
295   
296  a.  Randomized, double-blind, placebo-controlled RSV challenge trials in healthy adults 
297  who have received the investigational drug before inoculation with an acceptable 
298  RSV challenge strain.  Sponsors should discuss endpoints with the Agency; one 
299  possibility is prevention of symptomatic laboratory-confirmed RSV infection. 
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300   
301  b.  Randomized, double-blind, comparative trials of RSV prophylaxis in elderly and/or 
302  immunocompromised adults in centers, institutions, or regions in which widespread 
303  RSV disease activity has been documented.  Sponsors should discuss endpoints with 
304  the Agency; one possibility is the incidence of laboratory-confirmed, symptomatic 
305  RSV infection. 
306   
307  c.  Randomized, double-blind, placebo-controlled, comparative treatment trials of 
308  immunocompromised and/or elderly adults with acute symptomatic RSV infection.  
309  Trials could provide evidence of proof of concept that would support potential use for 
310  RSV prophylaxis.  Patients should have established infection before receiving the 
311  investigational drug.  Many endpoints could be explored in phase 2 trials, such as 
312  changes in RSV viral load, changes in RSV-specific sign and symptom assessment 
313  scores, duration of hospitalization, and other indicators of disease progression or 
314  resolution.  
315   
316  (3) Phase 2 pediatric studies for treatment and prophylaxis.  After proof of concept and 
317  safety in adults have been demonstrated, pediatric patients can be enrolled.  Generally, 
318  the initial pediatric study should be small, but could be expanded after safety is 
319  demonstrated in the initial cohort.  The pediatric study design should be similar to adult 
320  trial design (i.e., randomized, double-blind, placebo-controlled, dose-ranging trials), but 
321  different endpoints may be appropriate for the pediatric population because the disease 
322  course may be different (e.g., wheezing is prominent in children but not in adults).   
323   
324  To identify a potentially safe and effective dose to be confirmed in phase 3 for the intended 
325  population, robust dose-ranging trials should be considered in phase 2 before initiation of phase 
326  3 trials.  The initial dose selection in pediatrics should be based on 
327  pharmacokinetic(PK)/pharmacodynamic (PD) data (if available), safety data from adult phase 1 
328  and phase 2 trials, antiviral activity data from cell culture and animal models, and the safety data 
329  from nonclinical juvenile animal toxicology studies.  PD data can include, as described in 
330  III.A.2.b.(1)(b), changes in RSV viral load, and improvement in signs or symptoms.  Additional 
331  clinical pharmacology evaluations may be needed to assess appropriate dose adjustments for 
332  specific populations, including for patients with hepatic or renal impairment or patients taking 
333  concomitant medications.6  
334   
                                                 
6 For information on specific populations and drug-drug interactions, see the guidance for industry 
Pharmacokinetics in Patients with Impaired Hepatic Function:  Study Design, Data Analysis, and Impact on Dosing 
and Labeling and the draft guidances for industry Pharmacokinetics in Patients with Impaired Renal Function  
Study Design, Data Analysis, and Impact on Dosing and Labeling and Drug Interaction Studies  Study Design, 
Data Analysis, Implications for Dosing, and Labeling Recommendations.  When final, these guidances will 
represent the FDAs current thinking on these topics. 
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335  c.  Data needed to proceed to phase 3 
336   
337  For an end-of-phase 2 meeting, data from phase 2 trials, including all pharmacokinetic, safety, 
338  proof of concept, and antiviral activity data, should be available to support progression to phase 
339  3.  Data from all regimens under study in the drug development program should be used to select 
340  appropriate drug regimens and patient populations for study in phase 3.  
341   
342  3.  Dose Selection 
343   
344  The following recommendations on dose selection are not definitive and may vary between drug 
345  development programs depending on the characteristics of an individual drug as well as the 
346  proposed indication and patient population.  Additional consideration may be given to other drug 
347  development plans or clinical trial designs as warranted.  FDA encourages sponsors to engage in 
348  discussions on dose selection with the DAVP as early as possible.   
349   
350  The dose selected for phase 3 trials should be based on the exposure-response relationships 
351  established in phase 2 studies in pediatrics.  Different dosing strategies based on patient factors 
352  (e.g., body weight) may be appropriate to achieve target exposures, and prospective dose 
353  adjustment based on such factors should be considered in phase 3.  The safety and efficacy of the 
354  selected dose or doses should be further evaluated and confirmed in phase 3 trials.  
355   
356  For some drugs, more than one route of administration can be considered; however, different 
357  dosing, safety, and efficacy issues may arise with different routes of administration.  For 
358  example, an oral form may be desirable for moderate RSV disease whereas an intravenous 
359  formulation may be more desirable for seriously ill patients who may not be able to take oral 
360  formulations.  For inhalational routes, determining appropriate initial dosing for clinical trials 
361  can be challenging.  Using appropriate safety precautions and monitoring, sponsors should 
362  evaluate the safety of drugs delivered by inhalational routes initially in adults without and then 
363  with preexisting pulmonary disease because individuals with pulmonary disease may be at high 
364  risk for adverse reactions caused by inhalational drugs.  
365   
366  4.  Drug Development Population 
367   
368  Phase 3 clinical development programs for pediatric treatment and prophylaxis indications 
369  should focus initially on patient groups at risk for severe illness because the risk-benefit 
370  considerations are likely most favorable for these groups.  Based on the epidemiology of RSV 
371  disease, the population at most significant risk includes infants and children younger than 24 
372  months of age.  The risk of severe RSV LRTI is highest in infants younger than 6 months of age, 
373  infants born prematurely who are younger than 1 year of age, and infants and children younger 
374  than 24 months of age with either cyanotic congenital heart disease (CHD) or chronic lung 
375  disease of prematurity (CLD).   
376   
377  In addition to the pediatric population, RSV LRTI can also be severe in elderly patients, and 
378  RSV drugs (for treatment and prophylaxis) could potentially be evaluated in this population.  
379  Additional high-risk populations to consider for RSV clinical trials include immunocompromised 
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380  patients (e.g., hematopoietic stem cell or lung transplant recipients) and patients with chronic 
381  lung disease such as cystic fibrosis.  
382   
383  Protocols with a range of both Northern and Southern Hemisphere clinical investigational sites 
384  may increase efficiency of drug development by allowing data collection during different RSV 
385  seasons.  When sponsors rely on foreign clinical trial data  whether from multinational trials 
386  that include the United States or from trials conducted entirely outside the United States  to 
387  support the marketing approval of candidate drugs, sponsors should supplement the foreign data 
388  with information about circulating RSV strains, patterns of clinical illness, trial population 
389  demographics, standards of medical care, and the use of other medical interventions in the 
390  countries where the trials were conducted.  Sponsors should evaluate the relevance of foreign 
391  data under applicable FDA regulations considering trial conduct standards, trial population 
392  demographics, availability of sites for regulatory inspection, and applicability of disease 
393  manifestations and the standard medical care compared to that in the United States.  Sponsors 
394  also can consult the guidance for industry and FDA staff FDA Acceptance of Foreign Clinical 
395  Studies Not Conducted Under an IND Frequently Asked Questions. 
396   
397  5.  Efficacy Considerations 
398   
399  In general, treatment and prophylaxis indications should each be supported by two adequate and 
400  well-controlled trials.  However, sometimes a single persuasive trial may be sufficient for each 
401  indication depending on other supportive evidence.  In general, two trials that differ in design 
402  parameters and populations are more useful than two identically designed trials or a single large 
403  trial.  For example, one treatment trial in adults and one treatment study in children may be 
404  considered sufficient to support a treatment indication in adults and children.  In addition, one 
405  prophylaxis trial and one treatment trial may also be sufficient for consideration of an initial 
406  marketing application for both indications in some populations.   
407   
408  6.  Safety Considerations 
409   
410  At least 100 adults should be exposed to the drug (at exposures similar to or higher than that 
411  expected with the proposed pediatric dosage regimen) in clinical trials before initiating pediatric 
412  studies.  However, depending on the nonclinical pharmacology and toxicology findings and the 
413  preliminary pharmacokinetic and safety profile of the drug observed in adults, additional data in 
414  adults may be needed before initiation of pediatric studies.  The initial evaluation in pediatric 
415  patients should be small to characterize pharmacokinetics and to provide preliminary safety data.  
416  If no safety or tolerability issues are identified in the initial cohort, then sponsors can expand the 
417  evaluations.  
418   
419  A robust safety database from adequately blinded, well-controlled clinical trials in appropriate 
420  populations is important because of the wide variety of affected populations with a range of 
421  comorbidities that could interact with both disease and treatment.  The size of the safety database 
422  needed for a new drug application depends on the risk-benefit profile of the drug, the proposed 
423  indication or indications, and the weight of evidence from nonclinical toxicology studies.  For 
424  both treatment and prophylaxis trials, the safety population should consist of patients who are 
425  exposed to the proposed or higher level dose for the proposed duration of therapy.  For treatment 
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426  of severe RSV disease (e.g., bronchiolitis in pediatric patients, RSV pneumonia in adults), 300 to 
427  500 patients are recommended; while for prophylaxis indications or for treatment of mild to 
428  moderate RSV disease, a minimum of 1,500 patients are recommended for an adequate safety 
429  assessment.   
430   
431  Immunogenicity is a potential concern with any therapeutic biological product, and early clinical 
432  trials with these products should evaluate the potential effects on pharmacokinetics, safety, and 
433  efficacy (see the guidance for industry Immunogenicity Assessment for Therapeutic Protein 
434  Products). 
435   
436  Sponsors should provide adequate rationale for proposing specific populations for evaluation of 
437  drugs for RSV prophylaxis.  If the risk-benefit assessment of the investigational drug is 
438  favorable, evaluation of the drug for RSV prophylaxis in lower risk patients may be appropriate.   
439   
440  Trials that have vulnerable populations enrolled, such as infants and young children, will likely 
441  need a data monitoring committee.  
442   
443  B.  Phase 3 Efficacy Trial Considerations 
444   
445  1.  Trial Design 
446   
447  a.  Treatment of RSV LRTI 
448   
449  In the absence of a generally accepted standard-of-care antiviral treatment for acute bronchiolitis 
450  in infants and children, a randomized, double-blind, placebo-controlled trial in infants may be 
451  appropriate to demonstrate efficacy of the drug.  In this case, the investigational drug could be 
452  added to the current standard-of-care treatment (currently supportive care) compared to standard-
453  of-care therapy plus placebo.  In circumstances where aerosolized ribavirin is considered the 
454  standard of care for RSV bronchiolitis, the investigational drug can be evaluated as an add-on 
455  therapy to aerosolized ribavirin and compared to aerosolized ribavirin and placebo in a 
456  superiority trial.  Noninferiority trials comparing the investigational drug to ribavirin are not 
457  feasible because the registrational ribavirin trials used endpoints that are no longer clinically 
458  relevant and do not allow for calculation of a noninferiority margin (Hall, McBride, et al. 1983; 
459  Taber, Knight, et al. 1983).  Depending on the findings of clinical trials in phase 2, additional 
460  dose finding may be needed in phase 3 to optimize the dosing regimen.  The design of proposed 
461  clinical trials should also depend on the drug formulation and the route of administration.   
462   
463  After safe and effective anti-RSV drugs become available for treatment of RSV LRTI, placebo-
464  controlled trials may no longer be appropriate (e.g., trials evaluating serious or life-threatening 
465  infection), and trials should include an active control arm using a superiority or noninferiority 
466  design.  If a noninferiority design is proposed, justification for the noninferiority margin should 
467  be submitted to the DAVP for review and concurrence. 
468   
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469  b.  Prophylaxis for severe RSV LRTI 
470   
471  Several factors influence the design of RSV prophylaxis trials, including the type of drug (e.g., 
472  monoclonal antibody, small molecule), its PK and PD properties, and its therapeutic target as 
473  well as the safety profile of the drug or drug class.   
474   
475  Use of an active-controlled versus placebo-controlled trial design depends on the population 
476  being studied.  Randomized, double-blind trials comparing the investigational drug to an 
477  approved prophylactic drug may be appropriate for populations for which RSV prophylaxis is 
478  considered the current standard of care.  Such trials could evaluate superiority to the active 
479  comparator; noninferiority trials can also be considered if a noninferiority margin is determined 
480  and adequately justified (see III.B.6., Use of Active Comparators).  Placebo-controlled 
481  superiority trials may be appropriate for populations for which RSV prophylaxis is not approved 
482  or considered the current standard of care. 
483   
484  2.  Trial Population 
485   
486  For treatment indications, sponsors should justify the pediatric patient populations evaluated in 
487  the initial pediatric studies.  Sponsors should take multiple considerations into account, including 
488  the likelihood of demonstrating clinical benefit in specific populations and safety issues with the 
489  drug, which could have a focused use initially in patients who have severe illness or are at risk of 
490  severe LRTI disease.   
491   
492  For RSV prophylaxis indications in pediatric patients, initial pivotal studies should be conducted 
493  in those patients at increased risk for developing moderate-to-severe RSV LRTI (i.e., infants and 
494  children younger than 24 months of age).  For prophylaxis trials, enriching the population of 
495  patients at risk for severe RSV disease, such as premature infants who are in their first year of 
496  life or infants with CHD or CLD in the first two years of life, may help to better define the 
497  efficacy of the drug.  Sponsors could also consider enriching the population by studying ethnic or 
498  racial groups more prone to severe illness (Bockova, OBrien, et al. 2002). 
499   
500  3.  Entry Criteria  
501   
502  For treatment trials, patients should be enrolled based on the presentation of symptoms consistent 
503  with RSV LRTI.  Signs and symptoms defining LRTI should be specified in the inclusion criteria 
504  of the clinical protocol.  Diagnostic assays, such as rapid antigen tests, can be used at the time of 
505  subject screening to limit enrollment to individuals most likely to be infected, thereby enriching 
506  the patient population.  However, the potentially limited sensitivities of some diagnostic assays 
507  (e.g., rapid antigen tests) may inadvertently exclude some patients with RSV infection from 
508  enrollment thereby increasing the number of prospective patients to be screened and introducing 
509  a bias in enrollment (i.e., the trial population might reflect those patients who are infected with 
510  strains for which the screening assay is sensitive rather than representing patients with clinically 
511  significant infections).  In any case, RSV infections should be confirmed by a central laboratory 
512  using a sensitive assay (e.g., real-time reverse transcription polymerase chain reaction (RT-
513  PCR)).  
514   
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515  Because RSV coinfections with other respiratory viruses may be common and because the 
516  contribution of viral coinfection to symptom resolution is not known, coinfections should be 
517  documented and sensitivity analyses should be performed to evaluate treatment efficacy in 
518  patients with and without viral coinfections.  In cases where the investigational RSV antiviral 
519  drug has a broad spectrum of antiviral activity (including, for example, against other 
520  paramyxoviruses such as metapneumovirus), sensitivity analyses are even more important.  
521  Alternatively, stratification by the presence or absence of other respiratory virus coinfection 
522  could be considered.  In general, unlike influenza, RSV LRTI is not associated with a 
523  concomitant or secondary bacterial respiratory tract infection.  Therefore, FDA recommends the 
524  exclusion of patients with potential concomitant bacterial respiratory tract infections requiring 
525  treatment with antibacterial drugs. 
526   
527  For prophylaxis trials in infants and young children, all patients should have at least one risk 
528  factor for severe RSV infection, such as prematurity, young chronological age at the onset of 
529  RSV season, or a comorbid disease, as previously discussed.  Patients with a history of 
530  hypersensitivity to immunoglobulin preparations should be excluded from immunoprophylaxis 
531  trials.  Patients who receive another RSV prophylactic drug during the same RSV season should 
532  also be excluded.   
533   
534  4.  Randomization, Stratification, and Blinding 
535   
536  Clinical trials for prophylaxis and treatment indications should be randomized, double blind, and 
537  controlled.  Given the subjectivity of endpoints and the potential for variability in the course of 
538  RSV disease, double blinding of treatment group assignment is important to reduce bias.  In 
539  cases where blinding is not considered feasible (e.g., use of an injectable placebo control in 
540  pediatric studies of an injectable investigational formulation), additional measures should be 
541  taken to minimize bias and ensure integrity of randomization.  
542   
543  Stratification factors to consider include known risk factors for moderate-to-severe RSV LRTI, 
544  such as gestational and chronological age, comorbid conditions (e.g., CHD or CLD), and 
545  geographic region.  For treatment indications, stratification factors to consider include prior 
546  prophylaxis with palivizumab in the same RSV season, severity of RSV disease, and coinfection 
547  with other respiratory viruses.   
548   
549  5.  Other Populations 
550   
551  Although the majority of severe RSV infections occur in young infants, several other populations 
552  are at risk for severe RSV disease.  HSCT patients of any age can have severe life-threatening 
553  disease with RSV, and this population has a substantial need for RSV drugs.  Depending on the 
554  state of stem cell engraftment, HSCT patients may benefit from treatment of RSV infections 
555  confined to the upper respiratory tract to reduce progression to the lower respiratory tract.  The 
556  severity of RSV disease may be dependent on the degree of immune suppression, with some 
557  patients being at higher risk because of the nature of their transplants and the need for a high 
558  degree of immune suppression.  Other populations at risk for severe RSV disease include 
559  patients with cystic fibrosis and older adults, especially those residing in long-term care 
560  facilities. 
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561   
562  6.  Use of Active Comparators  
563   
564  In randomized, controlled treatment trials in which a placebo is not considered appropriate, 
565  active-controlled trials in which the comparator is an FDA-approved drug or considered the 
566  standard of care for the indication may be appropriate (e.g., ribavirin for treatment of RSV LRTI 
567  in bone marrow transplant patients).  If a noninferiority trial design is considered, then a 
568  noninferiority margin should be proposed, justified, and discussed with the DAVP because a 
569  noninferiority trial may not always be considered appropriate.7  See section III.B.1.a., Treatment 
570  of RSV LRTI, for further discussion about appropriate comparators.   
571   
572  An active control should be used in prophylaxis trials that include pediatric patients for whom 
573  RSV prophylaxis is currently recommended.  Placebo-controlled trials may be appropriate for 
574  populations for which RSV prophylaxis is not recommended per local standard of care.  Active-
575  controlled trials can be designed as superiority or noninferiority trials.  Prevention of 
576  hospitalization was used as the primary endpoint to support approval of palivizumab.  A 
577  noninferiority margin can be determined for prophylaxis studies in which palivizumab is the 
578  comparator for the endpoint of hospitalization (or another agreed upon similar endpoint 
579  demonstrated to be robust in a clinical trial) based on the treatment difference between 
580  palivizumab and placebo for the same or similar population.  Sponsors should discuss 
581  construction of an appropriate noninferiority margin with the DAVP.  
582   
583  7.  Efficacy Endpoints 
584   
585  Currently, efficacy endpoints have not been definitively established for clinical trials of RSV 
586  treatment or prophylaxis; sponsors should work closely with the DAVP to identify reliable and 
587  robust endpoints for treatment and prophylaxis of RSV disease of varying severity.  For 
588  treatment of RSV disease, a surrogate marker that reasonably predicts clinical response has not 
589  been identified.  Changes in RSV viral load may be informative for dose-ranging phase 2 PK/PD 
590  analysis, but at this time, primary endpoints in phase 3 trials should be clinical outcome 
591  measures.  In addition, virologic surrogates are not expected to offer an advantage over clinical 
592  endpoints because changes in both occur over the same time course. 
593   
594  Exploration of multiple secondary endpoints, including clinical and virological endpoints, is 
595  strongly advised in phase 2 trials to show consistency of effect with the primary endpoint and to 
596  inform selection of endpoints for pivotal phase 3 trials.  Protocol submissions should include and 
597  discuss prospectively the rationale for both primary and secondary endpoints. 
598   
599  a.  Treatment 
600   
601  The primary efficacy endpoint should assess improvement in clinical signs and symptoms of 
602  RSV disease.  RSV disease is typically short in duration (less than 2 weeks in most children), 
603  which allows for assessment of a primary clinical endpoint in a reasonable time frame in a 
                                                 
7 See the guidance for industry Non-Inferiority Clinical Trials to Establish Effectiveness.  
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604  clinical trial setting, obviating the need for a surrogate measure of efficacy (El Saleeby, Bush, et 
605  al. 2011; DeVincenzo, Whitley, et al. 2014). 
606   
607  The primary endpoint for treatment of RSV bronchiolitis could be time to a clinically 
608  meaningful, defined level of improvement.  Another option for the primary endpoint could be the 
609  degree of improvement/resolution of signs and symptoms using a multipoint scale at a 
610  prespecified time point.  Instruments for sign and symptom measurement should be developed 
611  and standardized to reliably and reproducibly measure signs and symptoms of RSV disease.  
612  Relevant elements could include signs such as tachypnea, hypoxia, and chest wall retractions as 
613  well as symptoms such as cough, wheezing, lethargy, and poor feeding.  Some signs, such as 
614  fever, tachypnea, and accessory muscle use, may resolve more quickly whereas other symptoms, 
615  such as wheezing and cough, may persist and could be assessed separately as coprimary or 
616  secondary endpoints.  Sponsors should provide adequate justification for proposed endpoints and 
617  the instruments used for sign and symptom assessment. 
618   
619  Patient-reported outcome (PRO) tools could be considered to assess symptoms in adults and 
620  children who can reliably self-report.  For patient populations that are unable to self-report (e.g., 
621  infants, young children, cognitively impaired), an observer-reported outcome (ObsRO) tool 
622  could potentially be used to assess observable RSV-related signs, events, and behaviors.  
623  Because no validated sign and symptom scoring system for RSV disease exists at this time, 
624  sponsors should propose and provide justification for a standardized or well-studied instrument 
625  for sign and symptom measurement and consult with FDA to develop well-defined and reliable 
626  instruments.  For further details regarding PRO and ObsRO development, refer to the guidance 
627  for industry Patient-Reported Outcome Measures:  Use in Medical Product Development to 
628  Support Labeling Claims.  Although not a regulatory requirement, the Drug Development Tools 
629  Qualification Programs provide FDA consultation and advice on tools such as PRO and ObsRO 
630  instruments that, once qualified, will be publicly available for use in multiple drug development 
631  programs over time.8 
632   
633  Secondary and exploratory endpoints can include:  
634   
635    Virologic assessments  
636    Prevention of hospitalization  
637    Prevention of disease progression, including prevention of intensive care unit admission  
638    Duration of supplemental oxygen use 
639    Duration of hospitalization  
640    Need for noninvasive positive-pressure ventilation or mechanical ventilation 
641    Duration of persistent symptoms such as wheezing and cough  
642   
643  Given that patients with RSV disease may be hospitalized and remain hospitalized for a variety 
644  of reasons (e.g., respiratory compromise, the inability to take oral hydration or nutrition), 
                                                 
8 See the FDA web page Drug Development Tools Qualification Programs at 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/.  
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645  interpretation of endpoints such as prevention of hospitalization or duration of hospitalization 
646  may not always be straightforward.  
647   
648  b.  Prophylaxis  
649   
650  In pediatric studies, the primary endpoint for prophylaxis studies should be the occurrence of 
651  laboratory-confirmed RSV LRTI.  In the past, prevention of RSV-related hospitalization was 
652  used for approval of RSV immunoprophylactic drugs in pediatric patients; however, the utility of 
653  prevention of RSV-related hospitalization as a primary endpoint has diminished as outpatient 
654  management of RSV has improved and as patients with more serious RSV disease are managed 
655  more often in the outpatient setting. 
656   
657  There has been considerable interest in the use of RSV prophylactic drugs to prevent wheezing 
658  or asthma later in childhood.  Assessment of long-term outcomes on symptoms such as wheezing 
659  is not required for FDA marketing approval, but clinical trials could be designed to evaluate a 
660  drugs effect on wheezing or the development of asthma.  Sponsors should be aware that the 
661  more meaningful endpoint is prevention of asthma rather than reduction of long-term wheezing; 
662  however, the Agency acknowledges that the studies evaluating prevention of asthma are longer 
663  in duration and more difficult to conduct.  Sponsors that plan to seek an indication for prevention 
664  of long-term wheezing should discuss their plans with the Agency, because there may be unique 
665  considerations with respect to trial design and endpoints that are beyond the scope of this 
666  guidance. 
667   
668  In adult trials, possible endpoints for prophylaxis could include prevention of all symptomatic 
669  respiratory infections, RSV LRTI (pneumonia), or progression of RSV upper respiratory tract 
670  infection to LRTI.  
671   
672  8.  Trial Procedures and Timing of Assessments 
673   
674  For treatment trials, intensive clinical assessments are important in the period shortly after 
675  treatment initiation because the typical self-limited disease course in otherwise healthy children 
676  may limit the ability to detect treatment effects at later time points.  Clinical assessments should 
677  be made at least three times daily.  Virologic assessments should be performed by a central 
678  laboratory using clinical samples obtained at presentation and at prespecified intervals 
679  throughout the clinical course.  These assessments should include quantitative RSV RT-PCR and 
680  quantitative RSV culture.  Clinical assessments can include serial measurement of respiratory 
681  rate, oxygen saturation, work of breathing, and ability to maintain hydration through oral intake. 
682   
683  In prophylaxis trials, all patients who develop RSV bronchiolitis or pneumonia (i.e., prophylaxis 
684  failures) should undergo virologic assessments performed by a central laboratory to confirm 
685  RSV infection.  These assessments should include quantitative RSV RT-PCR and quantitative 
686  RSV culture.  Because of the possibility of coinfection, diagnostic tests that detect multiple 
687  respiratory viruses should be performed.  Performance characteristics and descriptions of the 
688  virologic assays should be provided in clinical trial protocols.  Currently, an international 
689  standard is not available for quantification of RSV RNA.  Sponsors should include a readily 
690  available reference for interstudy comparisons in their assays. 
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691   
692  Treatment trials should include at least 21 days of follow-up to detect symptom recurrence after 
693  initial improvement, late-onset adverse events, or emergence of a resistant virus.  Follow-up for 
694  prophylaxis trials should continue for five half-lives of the drug to assess late-onset safety 
695  events.  Length of follow-up for treatment or prophylaxis studies may need to be longer 
696  depending on the population (e.g., immunocompromised patients with prolonged viral shedding). 
697   
698  9.  Statistical Considerations 
699   
700  Sponsors should provide a protocol with a statistical analysis plan for review and concurrence 
701  before initiating patient enrollment.  For treatment trials, the primary efficacy analyses should 
702  focus on the population with laboratory-confirmed RSV infections, a baseline characteristic, 
703  even if RSV infection is not confirmed until after baseline data are collected.  Given the 
704  likelihood that treatment decisions in clinical practice would be made before confirmation of 
705  diagnosis, analyses of safety data should be based on all randomized patients.  For prophylaxis 
706  trials, the primary efficacy analysis should include all patients who are randomized and receive 
707  at least one dose of assigned treatment during the trial.   
708   
709  In noninferiority trials, the choice of a noninferiority margin for statistical hypotheses should be 
710  discussed and agreed upon with the DAVP before study initiation.  Sponsors should determine a 
711  reliable control treatment effect (M1) based on historical evidence of the quantitative 
712  contribution of the active control.  This contribution should be determined in trials evaluating a 
713  similar population with similar length of follow-up as the proposed trial.  In addition, the 
714  noninferiority margin should be smaller than the M1 to preserve a clinically important effect 
715  compared to an active control.  For noninferiority testing, sponsors should employ two-sided, 95 
716  percent confidence intervals adjusted for multiple comparisons or other appropriate testing 
717  procedures.  For additional information regarding noninferiority studies, see ICH E10 and the 
718  guidance for industry Non-Inferiority Clinical Trials to Establish Effectiveness.  
719   
720  Sponsors should provide adequate details regarding the design, hypothesis, primary and 
721  secondary analyses, control of family-wise type I error rate, and any assumptions for the 
722  proposed sample size.  If sponsors consider more than one primary endpoint, sponsors should 
723  adjust the sample size at the planning stage to ensure sufficient power.  FDA recommends a 
724  stratified analysis when a trial is to be conducted in a heterogeneous population in which specific 
725  characteristics might affect the magnitude of the treatment effect.  Such specific characteristics 
726  or factors should be prespecified and considered for stratified randomization.  In these short-term 
727  trials, sponsors should avoid censoring patients in the intent-to-treat infected population.  
728  Missing data should be controlled and minimized, and the sponsor should have an explicit and 
729  adequate plan to address issues relating to missing data. 
730   
731  10.  Accelerated Approval (Subpart H) Considerations  
732   
733  Currently, no reasonably predictive surrogate endpoints are known for RSV disease in infants 
734  and young children, and accelerated approval of RSV drugs is not a feasible drug development 
735  pathway.  In addition, it is not clear that surrogate endpoints would be useful in accelerating drug 
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736  development because improvements in clinical symptoms can occur over the same time course 
737  as changes in virologic measurements. 
738   
739  11.  Risk-Benefit Considerations 
740   
741  RSV infection can result in a wide spectrum of illness in infants and young children from 
742  asymptomatic infection to RSV bronchiolitis and pneumonia.  Therefore, risk-benefit 
743  considerations are extremely important for the development of RSV drugs for infants and young 
744  children.  Because RSV drug development will likely focus on studies in pediatric patients (21 
745  CFR part 50, subpart D), risk-benefit assessments should be done for all drugs that are to be 
746  tested.  Depending on the patient population targeted (e.g., hospitalized patients with severe RSV 
747  disease versus those with milder RSV disease), different degrees of risk may be reasonable.  
748  However, any RSV drug targeting the entire infant population from birth to 12 months of age (or 
749  up to 2 years of age in children with CLD or CHD) to prevent progression of RSV disease should 
750  have a low risk profile to justify widespread use of the drug in children.   
751   
752  C.  Other Considerations 
753   
754  1.  Relevant Nonclinical Safety Considerations 
755   
756  General recommendations for supportive, nonclinical safety studies, including for the design and 
757  timing, are addressed in other FDA and ICH guidances for industry.  Small molecule drug 
758  development is discussed in the ICH guidances for industry M3(R2) Nonclinical Safety Studies 
759  for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals and 
760  M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing 
761  Authorization for Pharmaceuticals:  Questions and Answers (R2).  Recommendations for 
762  biologically derived drugs are discussed in the ICH guidance for industry S6(R1) Preclinical 
763  Safety Evaluation of Biotechnology-Derived Pharmaceuticals.  Nonclinical considerations 
764  specific to RSV drug development are discussed in this guidance.  
765   
766  In general, for small molecule drug development, FDA prefers that sponsors study the safety of 
767  new pharmaceuticals initially in adult clinical trials.  Nonclinical studies in two species of adult 
768  animals (rodent and nonrodent) are commonly conducted to support the first-in-human trials in 
769  healthy adults.9  If the small molecule pharmaceutical indication is intended primarily for a 
770  pediatric population, FDA recommends that sponsors conduct juvenile animal toxicology studies 
771  before initiation of pediatric studies to support the safety of the drug in the pediatric population.  
772  Depending on the proposed duration of the exposure in the pediatric population, long-term 
773  testing starting in juvenile animal toxicology studies may also be needed.  
774   
775  Drug development for biological products should employ a flexible and science-based approach.  
776  If the biological product indication is intended primarily for a pediatric population, sponsors 
                                                 
9 The FDA encourages sponsors to consult the FDA when considering a non-animal 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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777  should consider feasibility and potential utility of a nonclinical safety evaluation in a juvenile 
778  animal toxicology study.  
779   
780  2.  PK/PD Considerations 
781   
782  a.  PK measurement 
783   
784  The ability to measure drug exposures in the physiological compartment relevant to prophylaxis 
785  or treatment of RSV is dependent on the route of administration and the mechanism of action.  
786  For example, plasma concentrations may be easily quantifiable for drugs delivered via the oral or 
787  parenteral routes, but may be less so for drugs that are inhaled or administered intranasally.  
788  Additionally, plasma concentrations are more likely to reflect the systemic immunomodulatory 
789  activity of prophylactic drugs, and local exposures may be more correlated with the antiviral 
790  activity of drugs intended for treatment of RSV infection.  Thus, for drugs that are inhaled or 
791  delivered intranasally, drug concentrations in epithelial cells of the respiratory tract (estimated 
792  from nasal wash, sputum, and/or bronchoalveolar lavage) should be measured to evaluate the 
793  relationship of exposure and antiviral activity.  Invasive procedures such as bronchoalveolar 
794  lavage should be reserved for adult patients because the procedures are not done electively in 
795  pediatrics. 
796   
797  Regardless of the route of administration, plasma drug concentrations should be collected 
798  because the concentrations should be considered during safety assessments.  FDA recognizes 
799  that the collection of PK samples may be limited by the patient population under evaluation (e.g., 
800  pediatric patients); therefore, sample collection timelines should be designed to be maximally 
801  informative.   
802   
803  b.  PD measurement 
804   
805  The selection of robust and reproducible PD markers for antiviral activity against RSV is 
806  hindered by an incomplete understanding of RSV disease.  At present, FDA recommends the use 
807  of changes in RSV virological measures and clinical symptoms related to RSV disease as 
808  response metrics in exposure-response evaluations.  Sponsors should select response metrics 
809  based on biological plausibility, and relationships between selected response metrics and primary 
810  efficacy endpoints should be characterized.  During protocol development, the selected metrics 
811  should be discussed and agreed upon with the Agency.  Although information is limited, FDA 
812  encourages sponsors to relate dose/exposure-response observations from short-term measures to 
813  outcomes in phase 3 trials to inform dosing   
814   
815  The potential for clinical safety events to be exposure related should be assessed through 
816  exposure-response analyses.  Characterization of the relationship between drug exposure and 
817  toxicity will help to delineate the upper limit of tolerable drug exposure and to estimate the 
818  likelihood of an adverse event within a given exposure range. 
819   
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Draft  Not for Implementation 
820  c.  Modeling considerations 
821   
822  Sponsors should explore exposure-response relationships for efficacy and safety as early as 
823  possible during clinical development (e.g., following adult phase 2 trial or trials).  
824  Physiologically based pharmacokinetic analyses and/or population PK/PD analysis can be 
825  utilized.  Modeling should incorporate nonclinical antiviral activity, animal PK, safety, and PD 
826  data as appropriate, as well as data from adult phase 1 and phase 2 trials, and physiological 
827  difference between adults and infants to establish the initial dose to be evaluated in the first 
828  infant study.  This model should be refined on an ongoing basis as additional data become 
829  available.  It is not clear whether a model derived from adult and nonclinical data will be directly 
830  applicable to the infant data.  However, this model should be a starting point for continuous 
831  model development.  Sponsors should incorporate efficacy and safety data from placebo-
832  controlled arms into exposure-response models to allow for a clinically meaningful interpretation 
833  of the safety and efficacy of the investigational drug.  Sponsors should assess the influence of 
834  demographic and baseline factors on models as appropriate.  As with any drug development 
835  program, knowledge of the exposure-response relationships for efficacy and safety will facilitate 
836  dose selection in the primary patient population as well as for specific populations in which dose 
837  adjustments may be needed. 
838   
839  3.  Clinical Virology Considerations 
840   
841  a.  RSV diagnostic assays for screening and events 
842   
843  Diagnosis of RSV infection should be confirmed by a central laboratory using an assay or assays 
844  that are sensitive and specific for RSV A and RSV B.  Performance data for the central 
845  laboratory assay evaluating the geographically and temporally distinct isolates should be 
846  submitted to the FDA for review.  In addition, FDA recommends collecting any diagnostic 
847  laboratory results from local clinical sites participating in trials, including identification of the 
848  assay used. 
849   
850  Some RSV antiviral drugs might inhibit RSV diagnostic assays; for example, certain anti-RSV 
851  monoclonal antibodies have been shown to compete with the antibodies used in specific 
852  diagnostic assays, thereby reducing assay sensitivity (Deming, Patel, et al. 2013).  Sponsors 
853  should determine the effect of investigational drugs on the sensitivities of commercially available 
854  diagnostic assays, particularly those used in clinical trials.  These evaluations should be 
855  performed using drug concentrations consistent with drug use.  
856   
857  b.  Resistance analysis 
858   
859  Patients might fail RSV prophylaxis or treatment because of infection with a virus that is 
860  resistant to the investigational drug.  Resistant viruses may be transmitted (e.g., a patient is 
861  infected with a virus that harbors polymorphisms that affect drug susceptibility) or selected (i.e., 
862  a resistant virus is selected within a patient after replicating in the presence of the drug).  
863  Baseline and postfailure isolates from patients failing treatment should be genotypically 
864  characterized and compared to determine if a drug-resistant virus is present and, if so, if the 
865  resistant virus was present at baseline or selected within the patient.  If genotypic analysis of 
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Draft  Not for Implementation 
866  RSV isolates identifies the emergence of a virus expressing novel substitutions not previously 
867  analyzed during nonclinical resistance studies, the virus expressing those substitutions should be 
868  phenotypically characterized.  Sponsors should contact the DAVP to obtain the current format 
869  for submission of resistance data.  Sponsors proposing to use next generation sequencing should 
870  consult with the DAVP early in the process. 
871   
872  4.  Regulatory Considerations 
873   
874  Under the Pediatric Research Equity Act (Public Law 108-155) as amended by the Food and 
875  Drug Administration Reauthorization Act (Public Law 115-52), sponsors must submit an initial 
876  pediatric study plan (iPSP) to FDA no later than 60 days after the end-of-phase 2 meeting or at 
877  such time as may be agreed upon between FDA and the sponsor.10  However, sponsors are 
878  encouraged to begin discussions of their pediatric formulations and clinical development plans 
879  early in drug development.  The timing and content of the submission of an iPSP are described in 
880  detail in the draft guidance for industry Pediatric Study Plans:  Content of and Process for 
881  Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans.  As noted in 
882  the guidance, the iPSP should include the entire pediatric age range.  
883   
884   
                                                 
10 See section 505B(e)(2)(A)(ii) of the Federal Food, Drug, and Cosmetic Act (Public Law 75-717), as amended by 
section 506 of the Food and Drug Administration Safety and Innovation Act (Public Law 112-144) and the Food and 
Drug Administration Reauthorization Act (Public Law 115-52), and 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 FDAs current thinking on this topic. 
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Draft  Not for Implementation 
885  REFERENCES 
886   
887  American Academy of Pediatrics, Committee on Infectious Diseases and Bronchiolitis 
888  Guidelines Committee, 2014, Updated Guidance for Palivizumab Prophylaxis Among Infants 
889  and Young Children at Increased Risk of Hospitalization for Respiratory Syncytial Virus 
890  Infection, Pediatrics, 134(2):415420. 
891   
892  Arnold JJ, Sharma SD, Feng JY, Ray AS, Smidansky ED, Kireeva ML, Cho A, Perry J, Vela JE, 
893  Park Y, Xu Y, Tian Y, Babusis D, Barauskus O, Peterson BR, Gnatt A, Kashlev M, Zhong W, 
894  and Cameron CE, 2012, Sensitivity of Mitochondrial Transcription and Resistance of RNA 
895  Polymerase II Dependent Nuclear Transcription to Antiviral Ribonucleosides, PLoS Pathog, 
896  8(11):e1003030. 
897   
898  Bockova J, OBrien KL, Oski J, Croll J, Reid R, Weatherholtz RC, Santosham M, and Karron 
899  RA, 2002, Respiratory Syncytial Virus Infection in Navajo and White Mountain Apache 
900  Children, Pediatrics, 110(2 Pt 1):e20. 
901   
902  Deming DJ, Patel N, McCarthy MP, Mishra L, Shapiro AM, and Suzich JA, 2013, Potential for 
903  Palivizumab Interference With Commercially Available Antibody-Antigen Based Respiratory 
904  Syncytial Virus Diagnostic Assays, Pediatr Infec Dis J, 32(10):11441146. 
905   
906  DeVincenzo JP, Whitley RJ, Mackman RL, Scaglioni-Weinlich C, Harrison L, Farrell E, 
907  McBride S, Lambkin-Williams R, Jordan R, Xin Y, Ramanathan S, O'Riordan T, Lewis SA, Li 
908  X, Toback SL, Lin SL, and Chien JW, 2014, Oral GS-5806 Activity in a Respiratory Syncytial 
909  Virus Challenge Study, N Engl J Med, 371(8):711722.  
910   
911  El Saleeby CM, Bush AJ, Harrison LM, Aitken JA, and Devincenzo JP, 2011, Respiratory 
912  Syncytial Virus Load, Viral Dynamics, and Disease Severity in Previously Healthy Naturally 
913  Infected Children, J Infect Dis, 204(7):9961002. 
914   
915  Englund J, 1994, Passive Protection Against Respiratory Syncytial Virus Disease in Infants:  The 
916  Role of Maternal Antibody, Pediatr Infect Dis J, 13:449453. 
917   
918  Hall CB, McBride JT, Walsh EE, Bell DM, Gala CL, Hildreth S, Ten Eyck LG, and Hall WJ, 
919  1983, Aerosolized Ribavirin Treatment of Infants With Respiratory Syncytial Virus Infection.  A 
920  Randomized Double-Blind Study, N Engl J Med, 308(24):14431447.  
921   
922  Marroquin LD, Hynes J, Dykens JA, Jamieson JD and Will Y, 2007, Circumventing the Crabtree 
923  Effect:  Replacing Media Glucose With Galactose Increases Susceptibility of HepG2 Cells to 
924  Mitochondrial Toxicants, Toxicol Sci, 97(2):539547. 
925   
926  Ralston SL, Lieberthal AS, Meissner HC, Alverson BK, et al., 2014, Clinical Practice Guideline: 
927  The Diagnosis, Management, and Prevention of Bronchiolitis, Pediatrics, 134(5): e1474e1502. 
928   
929  Randolph AG and Wang EL,1996, Ribavirin for Respiratory Syncytial Virus Lower Respiratory 
930  Tract Infection, Arch of Pediatr Adolesc Med, 150(9):942947. 
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Draft  Not for Implementation 
931   
932  Smee DF, Hurst BL, Evans WJ, Clyde N, Wright S, Peterson C, Jung KH, Day CW, 2017, 
933  Evaluation of Cell Viability Dyes in Antiviral Assays with RNA Viruses That Exhibit Different 
934  Cytopathogenic Properties, J Virol Methods, 246:5157. 
935   
936  Taber LH, Knight V, Gilbert BE, McClung HW, Wilson SZ, Norton HJ, Thurson JM, Gordon 
937  WH, Atmar RL, and Schlaudt WR, 1983, Ribavirin Aerosol Treatment of Bronchiolitis 
938  Associated With Respiratory Syncytial Virus Infection in Infants, Pediatrics, 72(5):613618.   
939   
940  Viswanathan M, King V, Bordley C, et al., 2003, Management of Bronchiolitis in Infants and 
941  Children, Evidence Report/Technology Assessment No. 69:  U.S. Dept of Health and Human 
942  Services, Agency for Healthcare Research and Quality. 
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