Respiratory Syncytial Virus Infection: Developing Antiviral Drugs for Prophylaxis and Treatment Guidance for Industry

Administrative draft guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

17072dft.docx
10/06/17
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DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft
guidance.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

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

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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

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REFERENCES ............................................................................................................................ 22

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1
Respiratory Syncytial Virus Infection:	1
Developing Antiviral Drugs for Prophylaxis and Treatment	2
Guidance for Industry1
3
4
5
6
This draft guidance, when finalized, will represent the current thinking of the Food and Drug	7
Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not	8
binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the	9
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible	10
for this guidance as listed on the title page.	11
12
13
14
I. 	INTRODUCTION	15
16
The purpose of this guidance is to assist sponsors in the clinical development of drugs for the	17
treatment and prevention of disease caused by respiratory syncytial virus (RSV) infection.2
18
Specifically, this guidance addresses the Food and Drug Administration’s (FDA’s) current	19
thinking regarding the overall development program and clinical trial designs for the	20
development of drugs and biological products that support an indication for treatment and	21
prevention of disease caused by RSV infection. This draft guidance is intended to serve as a	22
focus for continued discussions among the Division of Antiviral Products (DAVP),	23
pharmaceutical sponsors, the academic community, and the public.3 This guidance focuses	24
primarily on the development of drugs with antiviral mechanism for RSV-related illness in	25
infants and young children (e.g., bronchiolitis) but also briefly discusses development for other	26
populations. The sections of this guidance that discuss nonclinical development are intended to	27
provide guidance regarding drug development for both prophylaxis and treatment.	28
29
This guidance does not address development of drugs that target the host response to RSV	30
infection, vaccines, or blood-derived products. This guidance does not contain discussion of the	31
general issues of statistical analysis or clinical trial design. Those topics are addressed in the	32
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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ICH guidances for industry E9 Statistical Principles for Clinical Trials and E10 Choice of	33
Control Group and Related Issues in Clinical Trials, respectively.4
34
35
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.	36
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only	37
as recommendations, unless specific regulatory or statutory requirements are cited. The use of	38
the word should in Agency guidances means that something is suggested or recommended, but	39
not required.	40
41
42
II. 	BACKGROUND	43
44
RSV has two subtypes, RSV A and RSV B, that may circulate concurrently, and both have been	45
associated with disease. RSV infections range from asymptomatic to severe and life-threatening	46
lower respiratory tract infection (LRTI). LRTI in infants and young children most commonly	47
presents as bronchiolitis, which is characterized by increased mucus production, bronchospasm,	48
and acute inflammation, edema, and necrosis of epithelial cells lining small airways	49
(Viswanathan, King, et al. 2003). Other manifestations of LRTI in all age groups include	50
pneumonia, as well as exacerbations of chronic lung disease such as asthma and chronic	51
obstructive pulmonary disease. All types of RSV LRTI are associated with a spectrum of illness	52
ranging from mild cough and wheezing to fulminant respiratory failure. Populations at high risk	53
for more severe disease include term infants younger than 6 months of age, preterm infants, older	54
adults, patients with chronic lung or cardiac disease, and immunocompromised patients,	55
particularly those who have undergone hematopoietic stem cell transplantation (HSCT).	56
57
Currently, there are no established definitions for disease severity in pediatric patients with RSV	58
bronchiolitis. Therefore, the following definitions are used for the purpose of this guidance.	59
Severe RSV bronchiolitis is characterized by signs and symptoms of LRTI (e.g., tachypnea,	60
nasal flaring, and hypoxemia) with obvious respiratory distress, accompanied by poor feeding.	61
Moderate RSV bronchiolitis is defined as symptomatic respiratory illness without overt	62
respiratory distress, which often requires additional caregiver activities (e.g., frequent nasal	63
suctioning, repositioning, changes to feeding schedule) to sustain normal daily activities.	64
Moderate disease is more likely to result in a visit to a health care provider than mild disease,	65
which is defined as symptomatic respiratory illness with limited disruption of daily activities	66
(e.g., feeding, sleeping).	67
68
One challenge in the development of drugs for treatment and prophylaxis of RSV disease in	69
pediatric patients is a lack of full understanding of the pathogenesis of RSV infection. The role	70
of RSV cytotoxicity versus that of the host immune response in RSV disease remains uncertain.	71
Therefore, optimal approaches for treatment and prophylaxis of RSV disease have not been	72
established.	73
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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Currently, two drugs are FDA approved for prevention or treatment of RSV LRTI in pediatric	75
patients: palivizumab for prophylaxis and aerosolized ribavirin for treatment. In 1996,	76
palivizumab (a monoclonal antibody that targets the RSV F protein) was approved for the	77
following indication:	78
79
prevention of serious lower respiratory tract disease caused by RSV in children at high risk	80
of RSV disease.	81
82
Palivizumab was initially approval based on the results of a double-blind placebo controlled	83
study of 1,502 patients 24 months of age or younger with bronchopulmonary dysplasia (BPD) or	84
infants with premature birth (35 weeks or less gestation) who were 6 months of age or younger at	85
study entry. In this study, reductions of RSV hospitalization were observed for both of these	86
high-risk groups. Among patients with BPD, 7.9% (39/496) of palivizumab patients were	87
hospitalized compared to 12.8% (34/266) of placebo patients. Among premature infants without	88
BPD, 1.8% (19/234) of palivizumab-treated pediatric patients were hospitalized compared to	89
8.1% (9/506) of pediatric patients who received placebo. The use of palivizumab in the United	90
States is largely guided by a clinical practice guideline published by the American Academy of	91
Pediatrics (AAP) in 2014 and the AAP’s 2014 guidance for palivizumab prophylaxis (Ralston,	92
Lieberthal, et al. 2014; AAP Committee on Infectious Diseases and Bronchiolitis Guidelines	93
Committee 2014). In 1985, FDA approved aerosolized ribavirin for treatment of hospitalized	94
infants and young children with severe LRTIs caused by RSV. The approval was based on two	95
small placebo-controlled studies in nonmechanically ventilated infants; the results of which were	96
subsequently published (Hall, McBride, et al. 1983; Taber, Knight, et al. 1983). On day 3 of	97
treatment, both studies showed statistically significant differences in mean symptom scores.	98
However, a subsequent meta-analysis by Randolph and Wang (1996) cited many methodological	99
errors in the studies that had supported aerosolized ribavirin’s clinical benefits, and the authors	100
concluded that treatment with aerosolized ribavirin failed to impart any clinically significant	101
benefits. At present, health care providers’ perceptions of limited clinical benefits, in addition to	102
concerns for mutagenicity, carcinogenicity, and teratogenicity with ribavirin, has resulted in	103
infrequent use of ribavirin for the treatment of RSV-associated illness. Currently, ribavirin is	104
used mainly when the outcome of an RSV LRTI could be fatal, such as in RSV infections in	105
bone marrow transplant patients.	106
107
108
III. 	DEVELOPMENT PROGRAM	109
110
A. 	General Drug Development Considerations	111
112
Sponsors considering development of antiviral drugs for the treatment of RSV infection are	113
encouraged to communicate with FDA through the pre-Investigational New Drug application	114
(pre-IND) consultation program.5 Pre-IND consultation with FDA is optional; although, it may	115
be particularly helpful for sponsors with limited experience in the IND process or to obtain FDA	116
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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advice in the development of drug products with unique considerations based on mechanistic	117
action or novel treatment approaches or the use of novel biomarkers.	118
119
The following sections address nonclinical virology, phase 1 and 2 trials, target population, and	120
overall efficacy and safety considerations.	121
122
1. 	Nonclinical Virology Development Considerations	123
124
The antiviral activity of an investigational drug should be determined using a cell culture model	125
of infection before submission of an initial investigational new drug application (IND).	126
Additional recommendations for antiviral drug development can be found in the guidance for	127
industry Antiviral Product Development — Conducting and Submitting Virology Studies to the	128
Agency.	129
130
a. 	Mechanism of Action	131
132
Ideally, sponsors should determine the mechanism by which a drug inhibits RSV. Mechanism of	133
action investigations should include an assessment of the drug’s specificity for the target and	134
should employ appropriate controls, such as uninfected cells, cells infected with viruses other	135
than RSV, and/or cells infected with drug-resistant RSV variants. Biochemical or subcellular	136
quantitative assays supporting the mechanism of action should report the 50 and 90 percent	137
inhibitory concentrations (IC 50 and IC 90 values).	138
139
b. 	Antiviral activity in cell culture	140
141
The antiviral activity of a new drug should be characterized using a cell culture model of RSV	142
infection to demonstrate activity and identify a target concentration for the initial clinical trials.	143
Antiviral activity studies should include assessments against a broad range of RSV A and RSV B	144
laboratory and clinical isolates, preferably representing multiple RSV seasons and different	145
geographic regions. The effective concentrations at which virus replication is inhibited by 50	146
and 90 percent (EC 50 and EC 90 values) should be determined using a quantitative assay. Also,	147
the sponsor should determine the effect of serum and mucosal proteins on antiviral activity and	148
calculate a protein binding-adjusted EC 50 value. Sponsors developing monoclonal antibodies	149
should evaluate the potential for antibody dependent enhancement of infection.	150
151
c. 	Cytotoxicity and mitochondrial toxicity	152
153
The cytotoxicity evaluation should make use of the same cells and culture conditions (e.g., drug	154
exposure durations) used for determining antiviral activity. A 50 percent cytotoxic concentration	155
(CC 50 ) and a therapeutic index (i.e., CC50 /EC 50 ) should be calculated. Sponsors may need to use	156
different assay methodologies to evaluate cytotoxicity (Smee, Hurst, et al. 2017) and should note	157
that cytotoxic effects that reduce viral replication may not manifest as cell death. Therefore,	158
assessments of cellular metabolism (e.g., transcription levels of cellular genes) may provide	159
more relevant measures of toxicity. The cytotoxicity evaluation should use multiple RSV-	160
susceptible human cell lines and primary cells cultured under proliferating and nonproliferating	161
conditions. Some investigational drugs (e.g., nucleos(t)ide analog inhibitors) should also be	162

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evaluated for inhibitory activity against host DNA polymerases, mitochondrial DNA	163
polymerases, and RNA polymerases, as well as for mitochondrial toxicity (Marroquin, Hynes, et	164
al. 2007; Arnold, Sharma, et al. 2012). Sponsors should note that these biochemical and cell-	165
based toxicity evaluations should not be considered substitutes for animal toxicity studies.	166
167
d. 	Combination antiviral activity	168
169
The combination antiviral activity of approved drugs, such as approved anti-RSV drugs, that are	170
likely to be used with an investigational drug should be evaluated early in drug development.	171
Combination antiviral activity determinations with other investigational drugs should be	172
conducted if the drugs may be used together in future trials or clinical practice. The combination	173
antiviral activity assessments should include concentrations spanning each drug’s EC 50 value,	174
when applicable, or relevant in vivo concentration. These studies should also include	175
combination cytotoxicity assessments.	176
177
e. 	Activity in animal models	178
179
Demonstrating anti-RSV activity using animal models of infection could be useful for	180
characterizing potential clinical use (e.g., prophylaxis or treatment, identifying the potential	181
therapeutic window) and for providing additional proof-of-concept data to support clinical	182
development. Sponsors can discuss with the DAVP the selection and use of animal models of	183
RSV infection before conducting studies.	184
185
f. 	Resistance and cross-resistance	186
187
Resistance studies are useful for identifying resistance pathways, determining genetic barriers to	188
resistance, assessing cross-resistance with other antiviral drugs, and providing additional data to	189
support the proposed mechanism of action. RSV variants that are resistant to an investigational	190
drug should be selected using a cell culture or animal model of infection and then genotypically	191
and phenotypically characterized. The effect of each selected amino acid substitution on	192
antiviral activity should be assessed individually and in combination using an RSV reverse	193
genetics system when feasible.	194
195
Resistance studies should include an evaluation of potential cross-resistance with approved	196
drugs. In addition, cross-resistance between investigational drugs should be completed for drug	197
combinations that may be used in clinical trials. The evaluation should include: (1) assessments	198
of the antiviral activity of the investigational drug against mutant viruses that are resistant to	199
other drugs and (2) assessments of the antiviral activities of other drugs against mutant viruses	200
that are resistant to the investigational drug. Evaluating cross-resistance is particularly important	201
for drugs belonging to the same class (e.g., nucleoside analog inhibitors) or targeting the same	202
viral protein or protein complex (e.g., fusion protein).	203
204
2. 	General Considerations for Phase 1 and Phase 2 Development	205
206
The primary objective of early clinical trials should be to establish pharmacokinetics, safety, and	207
antiviral activity and to provide sufficient data for study design and dose selection for phase 3	208

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trials. For most viral infections, efficacy of an antiviral drug is evaluated initially in adults and	209
extrapolated to the pediatric population if the pathophysiology of the disease is similar in adults	210
and pediatric patients. Then, generally, pharmacokinetics, safety, and antiviral activity of the	211
drug are evaluated in a smaller pediatric study. However, the pathophysiology of RSV disease is	212
thought to differ significantly between adult and pediatric patients. One of the key physiological	213
and anatomical differences between the respiratory tracts of infants and older children or adults	214
is that infants have smaller airways, which appear to be more susceptible to compromise from	215
inflammation caused by RSV infection. Therefore, extrapolation of efficacy data from adults to	216
pediatric patients is not possible for bronchiolitis and may not be possible for other types of RSV	217
LRTI in young children. Thus, sponsors should conduct fully powered clinical studies	218
evaluating efficacy and safety of an antiviral drug for treatment of RSV infection in pediatric	219
patients.	220
221
Before initiating pediatric studies, safety should be demonstrated in adult clinical trials and in	222
juvenile animal toxicology studies, as discussed in section III.C.1., Relevant Nonclinical Safety	223
Considerations. In addition, transition to pediatric studies depends on adequate demonstration of	224
proof of concept because, for any clinical investigation involving more than minimal risk, a	225
potential benefit for pediatric patients must exist (21 CFR 50.52). The types of trials to be	226
considered may differ for treatment and prophylaxis indications. In some cases, studies	227
demonstrating in vivo antiviral activity in well-characterized animal model or models of RSV	228
infection can also support initiation of pediatric clinical studies.	229
230
The following subsections provide general recommendations and examples for potential phase 1	231
and phase 2 trial designs for investigational drugs for RSV disease treatment or prophylaxis.	232
233
a. 	Phase 1a/First-in-human trials	234
235
Phase 1 trials should be conducted to assess safety and pharmacokinetics of the investigational	236
drug. In general, FDA recommends single- and/or multiple-ascending-dose trials in healthy	237
adult subjects to assess safety and pharmacokinetics for the first-in-human trials. Combined with	238
nonclinical virology data, these trials support dose selection for phase 2 trials.	239
240
b. 	Phase 2 trials	241
242
The primary objectives of phase 2 trials should be characterization of the safety profile and	243
demonstration of proof of concept in adults and children. Phase 2 trials should also identify the	244
optimal dose and treatment duration of the investigational drug with regard to pharmacokinetics,	245
safety, and antiviral activity. Below are three potential study designs for phase 2 trials in adults	246
and in children:	247
248
(1) Phase 2 RSV treatment trials in adults. Currently, it is not known whether demonstration	249
of antiviral (anti-RSV) activity in adults predicts efficacy in treatment of RSV LRTI in	250
infants and young children. However, obtaining evidence for proof of concept in adults	251
with symptomatic RSV infection supports the prospect of clinical benefit in infants and	252
young children. Therefore, FDA recommends evaluating both antiviral activity (using	253

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virological measurements) and clinical signs and symptoms in adults in early phase trials.	254
Possible trial design options for proof-of-concept clinical trials include:	255
256
a. 	Randomized, double-blind, placebo-controlled treatment trials in healthy adults	257
experimentally infected with an acceptable RSV challenge strain. Subjects who are	258
experimentally inoculated should have established infections before receiving the	259
investigational drug. Many endpoints could be explored such as changes in RSV	260
viral load, RSV-specific sign and symptom assessment scores, and mucus or tissue	261
weights.	262
263
b. 	Randomized, double-blind, comparative treatment trials of immunocompromised	264
and/or elderly adults with acute symptomatic RSV infection. Patients should have	265
established infections before receiving the investigational drug. Many endpoints	266
could be explored in phase 2 trials, such as changes in RSV viral load, changes in	267
clinical symptom scores, duration of hospitalization, and other indicators of disease	268
progression or resolution. A superiority trial comparing an investigational drug to	269
ribavirin or an add-on superiority trial compared to a placebo added to a background	270
of ribavirin could be considered for adult patients at institutions where ribavirin is	271
considered part of the standard of care for acute RSV disease (e.g.,	272
immunosuppressed patients). Placebo-controlled trials may be appropriate for	273
patients for whom no approved therapy exists and for whom ribavirin is not	274
considered standard of care.	275
276
Each of these trial designs has advantages and disadvantages. Although challenge trials	277
are simpler to conduct, demonstrating clinical benefit may be more difficult because	278
disease is mild and generally limited to the upper respiratory tract. Therefore, these trials	279
may only be useful to demonstrate antiviral activity. Randomized controlled trials of	280
naturally infected patients are logistically more complicated than challenge trials; the	281
former are more likely to enroll patients with clinically significant illness and lower	282
respiratory tract disease and are therefore more likely to be able to demonstrate a clinical	283
treatment benefit. Ultimately, data from both types of trials may be used together to	284
support further development for adult and pediatric indications.	285
286
(2) Phase 2 RSV prophylaxis trials in adults. Historically, development of prophylactic	287
drugs for RSV disease focused on passive immunoprophylaxis, defined as the prevention	288
of disease by the administration of antibodies. The scientific basis for	289
immunoprophylaxis of RSV disease is based on observational studies of RSV infection in	290
infants, which revealed a correlation between circulating maternal anti-RSV antibody	291
levels and decreased severity of disease (Englund 1994). Development of new drugs for	292
RSV prophylaxis may need proof-of-concept trials in adults before pediatric studies.	293
Examples of proof-of-concept trials in adults include the following:	294
295
a. 	Randomized, double-blind, placebo-controlled RSV challenge trials in healthy adults	296
who have received the investigational drug before inoculation with an acceptable	297
RSV challenge strain. Sponsors should discuss endpoints with the Agency; one	298
possibility is prevention of symptomatic laboratory-confirmed RSV infection.	299

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300
b. 	Randomized, double-blind, comparative trials of RSV prophylaxis in elderly and/or	301
immunocompromised adults in centers, institutions, or regions in which widespread	302
RSV disease activity has been documented. Sponsors should discuss endpoints with	303
the Agency; one possibility is the incidence of laboratory-confirmed, symptomatic	304
RSV infection.	305
306
c. 	Randomized, double-blind, placebo-controlled, comparative treatment trials of	307
immunocompromised and/or elderly adults with acute symptomatic RSV infection.	308
Trials could provide evidence of proof of concept that would support potential use for	309
RSV prophylaxis. Patients should have established infection before receiving the	310
investigational drug. Many endpoints could be explored in phase 2 trials, such as	311
changes in RSV viral load, changes in RSV-specific sign and symptom assessment	312
scores, duration of hospitalization, and other indicators of disease progression or	313
resolution.	314
315
(3) Phase 2 pediatric studies for treatment and prophylaxis. After proof of concept and	316
safety in adults have been demonstrated, pediatric patients can be enrolled. Generally,	317
the initial pediatric study should be small, but could be expanded after safety is	318
demonstrated in the initial cohort. The pediatric study design should be similar to adult	319
trial design (i.e., randomized, double-blind, placebo-controlled, dose-ranging trials), but	320
different endpoints may be appropriate for the pediatric population because the disease	321
course may be different (e.g., wheezing is prominent in children but not in adults).	322
323
To identify a potentially safe and effective dose to be confirmed in phase 3 for the intended	324
population, robust dose-ranging trials should be considered in phase 2 before initiation of phase	325
3 trials. The initial dose selection in pediatrics should be based on	326
pharmacokinetic(PK)/pharmacodynamic (PD) data (if available), safety data from adult phase 1	327
and phase 2 trials, antiviral activity data from cell culture and animal models, and the safety data	328
from nonclinical juvenile animal toxicology studies. PD data can include, as described in	329
III.A.2.b.(1)(b), changes in RSV viral load, and improvement in signs or symptoms. Additional	330
clinical pharmacology evaluations may be needed to assess appropriate dose adjustments for	331
specific populations, including for patients with hepatic or renal impairment or patients taking	332
concomitant medications.6
333
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 FDA’s current thinking on these topics.

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c. 	Data needed to proceed to phase 3	335
336
For an end-of-phase 2 meeting, data from phase 2 trials, including all pharmacokinetic, safety,	337
proof of concept, and antiviral activity data, should be available to support progression to phase	338
3. Data from all regimens under study in the drug development program should be used to select	339
appropriate drug regimens and patient populations for study in phase 3.	340
341
3. 	Dose Selection	342
343
The following recommendations on dose selection are not definitive and may vary between drug	344
development programs depending on the characteristics of an individual drug as well as the	345
proposed indication and patient population. Additional consideration may be given to other drug	346
development plans or clinical trial designs as warranted. FDA encourages sponsors to engage in	347
discussions on dose selection with the DAVP as early as possible.	348
349
The dose selected for phase 3 trials should be based on the exposure-response relationships	350
established in phase 2 studies in pediatrics. Different dosing strategies based on patient factors	351
(e.g., body weight) may be appropriate to achieve target exposures, and prospective dose	352
adjustment based on such factors should be considered in phase 3. The safety and efficacy of the	353
selected dose or doses should be further evaluated and confirmed in phase 3 trials.	354
355
For some drugs, more than one route of administration can be considered; however, different	356
dosing, safety, and efficacy issues may arise with different routes of administration. For	357
example, an oral form may be desirable for moderate RSV disease whereas an intravenous	358
formulation may be more desirable for seriously ill patients who may not be able to take oral	359
formulations. For inhalational routes, determining appropriate initial dosing for clinical trials	360
can be challenging. Using appropriate safety precautions and monitoring, sponsors should	361
evaluate the safety of drugs delivered by inhalational routes initially in adults without and then	362
with preexisting pulmonary disease because individuals with pulmonary disease may be at high	363
risk for adverse reactions caused by inhalational drugs.	364
365
4. 	Drug Development Population	366
367
Phase 3 clinical development programs for pediatric treatment and prophylaxis indications	368
should focus initially on patient groups at risk for severe illness because the risk-benefit	369
considerations are likely most favorable for these groups. Based on the epidemiology of RSV	370
disease, the population at most significant risk includes infants and children younger than 24	371
months of age. The risk of severe RSV LRTI is highest in infants younger than 6 months of age,	372
infants born prematurely who are younger than 1 year of age, and infants and children younger	373
than 24 months of age with either cyanotic congenital heart disease (CHD) or chronic lung	374
disease of prematurity (CLD).	375
376
In addition to the pediatric population, RSV LRTI can also be severe in elderly patients, and	377
RSV drugs (for treatment and prophylaxis) could potentially be evaluated in this population.	378
Additional high-risk populations to consider for RSV clinical trials include immunocompromised	379

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patients (e.g., hematopoietic stem cell or lung transplant recipients) and patients with chronic	380
lung disease such as cystic fibrosis.	381
382
Protocols with a range of both Northern and Southern Hemisphere clinical investigational sites	383
may increase efficiency of drug development by allowing data collection during different RSV	384
seasons. When sponsors rely on foreign clinical trial data — whether from multinational trials	385
that include the United States or from trials conducted entirely outside the United States — to	386
support the marketing approval of candidate drugs, sponsors should supplement the foreign data	387
with information about circulating RSV strains, patterns of clinical illness, trial population	388
demographics, standards of medical care, and the use of other medical interventions in the	389
countries where the trials were conducted. Sponsors should evaluate the relevance of foreign	390
data under applicable FDA regulations considering trial conduct standards, trial population	391
demographics, availability of sites for regulatory inspection, and applicability of disease	392
manifestations and the standard medical care compared to that in the United States. Sponsors	393
also can consult the guidance for industry and FDA staff FDA Acceptance of Foreign Clinical	394
Studies Not Conducted Under an IND Frequently Asked Questions.	395
396
5. 	Efficacy Considerations	397
398
In general, treatment and prophylaxis indications should each be supported by two adequate and	399
well-controlled trials. However, sometimes a single persuasive trial may be sufficient for each	400
indication depending on other supportive evidence. In general, two trials that differ in design	401
parameters and populations are more useful than two identically designed trials or a single large	402
trial. For example, one treatment trial in adults and one treatment study in children may be	403
considered sufficient to support a treatment indication in adults and children. In addition, one	404
prophylaxis trial and one treatment trial may also be sufficient for consideration of an initial	405
marketing application for both indications in some populations.	406
407
6. 	Safety Considerations	408
409
At least 100 adults should be exposed to the drug (at exposures similar to or higher than that	410
expected with the proposed pediatric dosage regimen) in clinical trials before initiating pediatric	411
studies. However, depending on the nonclinical pharmacology and toxicology findings and the	412
preliminary pharmacokinetic and safety profile of the drug observed in adults, additional data in	413
adults may be needed before initiation of pediatric studies. The initial evaluation in pediatric	414
patients should be small to characterize pharmacokinetics and to provide preliminary safety data.	415
If no safety or tolerability issues are identified in the initial cohort, then sponsors can expand the	416
evaluations.	417
418
A robust safety database from adequately blinded, well-controlled clinical trials in appropriate	419
populations is important because of the wide variety of affected populations with a range of	420
comorbidities that could interact with both disease and treatment. The size of the safety database	421
needed for a new drug application depends on the risk-benefit profile of the drug, the proposed	422
indication or indications, and the weight of evidence from nonclinical toxicology studies. For	423
both treatment and prophylaxis trials, the safety population should consist of patients who are	424
exposed to the proposed or higher level dose for the proposed duration of therapy. For treatment	425

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of severe RSV disease (e.g., bronchiolitis in pediatric patients, RSV pneumonia in adults), 300 to	426
500 patients are recommended; while for prophylaxis indications or for treatment of mild to	427
moderate RSV disease, a minimum of 1,500 patients are recommended for an adequate safety	428
assessment.	429
430
Immunogenicity is a potential concern with any therapeutic biological product, and early clinical	431
trials with these products should evaluate the potential effects on pharmacokinetics, safety, and	432
efficacy (see the guidance for industry Immunogenicity Assessment for Therapeutic Protein	433
Products).	434
435
Sponsors should provide adequate rationale for proposing specific populations for evaluation of	436
drugs for RSV prophylaxis. If the risk-benefit assessment of the investigational drug is	437
favorable, evaluation of the drug for RSV prophylaxis in lower risk patients may be appropriate.	438
439
Trials that have vulnerable populations enrolled, such as infants and young children, will likely	440
need a data monitoring committee.	441
442
B. 	Phase 3 Efficacy Trial Considerations	443
444
1. 	Trial Design	445
446
a. 	Treatment of RSV LRTI	447
448
In the absence of a generally accepted standard-of-care antiviral treatment for acute bronchiolitis	449
in infants and children, a randomized, double-blind, placebo-controlled trial in infants may be	450
appropriate to demonstrate efficacy of the drug. In this case, the investigational drug could be	451
added to the current standard-of-care treatment (currently supportive care) compared to standard-	452
of-care therapy plus placebo. In circumstances where aerosolized ribavirin is considered the	453
standard of care for RSV bronchiolitis, the investigational drug can be evaluated as an add-on	454
therapy to aerosolized ribavirin and compared to aerosolized ribavirin and placebo in a	455
superiority trial. Noninferiority trials comparing the investigational drug to ribavirin are not	456
feasible because the registrational ribavirin trials used endpoints that are no longer clinically	457
relevant and do not allow for calculation of a noninferiority margin (Hall, McBride, et al. 1983;	458
Taber, Knight, et al. 1983). Depending on the findings of clinical trials in phase 2, additional	459
dose finding may be needed in phase 3 to optimize the dosing regimen. The design of proposed	460
clinical trials should also depend on the drug formulation and the route of administration.	461
462
After safe and effective anti-RSV drugs become available for treatment of RSV LRTI, placebo-	463
controlled trials may no longer be appropriate (e.g., trials evaluating serious or life-threatening	464
infection), and trials should include an active control arm using a superiority or noninferiority	465
design. If a noninferiority design is proposed, justification for the noninferiority margin should	466
be submitted to the DAVP for review and concurrence.	467
468

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b. 	Prophylaxis for severe RSV LRTI	469
470
Several factors influence the design of RSV prophylaxis trials, including the type of drug (e.g.,	471
monoclonal antibody, small molecule), its PK and PD properties, and its therapeutic target as	472
well as the safety profile of the drug or drug class.	473
474
Use of an active-controlled versus placebo-controlled trial design depends on the population	475
being studied. Randomized, double-blind trials comparing the investigational drug to an	476
approved prophylactic drug may be appropriate for populations for which RSV prophylaxis is	477
considered the current standard of care. Such trials could evaluate superiority to the active	478
comparator; noninferiority trials can also be considered if a noninferiority margin is determined	479
and adequately justified (see III.B.6., Use of Active Comparators). Placebo-controlled	480
superiority trials may be appropriate for populations for which RSV prophylaxis is not approved	481
or considered the current standard of care.	482
483
2. 	Trial Population	484
485
For treatment indications, sponsors should justify the pediatric patient populations evaluated in	486
the initial pediatric studies. Sponsors should take multiple considerations into account, including	487
the likelihood of demonstrating clinical benefit in specific populations and safety issues with the	488
drug, which could have a focused use initially in patients who have severe illness or are at risk of	489
severe LRTI disease.	490
491
For RSV prophylaxis indications in pediatric patients, initial pivotal studies should be conducted	492
in those patients at increased risk for developing moderate-to-severe RSV LRTI (i.e., infants and	493
children younger than 24 months of age). For prophylaxis trials, enriching the population of	494
patients at risk for severe RSV disease, such as premature infants who are in their first year of	495
life or infants with CHD or CLD in the first two years of life, may help to better define the	496
efficacy of the drug. Sponsors could also consider enriching the population by studying ethnic or	497
racial groups more prone to severe illness (Bockova, O’Brien, et al. 2002).	498
499
3. 	Entry Criteria	500
501
For treatment trials, patients should be enrolled based on the presentation of symptoms consistent	502
with RSV LRTI. Signs and symptoms defining LRTI should be specified in the inclusion criteria	503
of the clinical protocol. Diagnostic assays, such as rapid antigen tests, can be used at the time of	504
subject screening to limit enrollment to individuals most likely to be infected, thereby enriching	505
the patient population. However, the potentially limited sensitivities of some diagnostic assays	506
(e.g., rapid antigen tests) may inadvertently exclude some patients with RSV infection from	507
enrollment thereby increasing the number of prospective patients to be screened and introducing	508
a bias in enrollment (i.e., the trial population might reflect those patients who are infected with	509
strains for which the screening assay is sensitive rather than representing patients with clinically	510
significant infections). In any case, RSV infections should be confirmed by a central laboratory	511
using a sensitive assay (e.g., real-time reverse transcription polymerase chain reaction (RT-	512
PCR)).	513
514

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Because RSV coinfections with other respiratory viruses may be common and because the	515
contribution of viral coinfection to symptom resolution is not known, coinfections should be	516
documented and sensitivity analyses should be performed to evaluate treatment efficacy in	517
patients with and without viral coinfections. In cases where the investigational RSV antiviral	518
drug has a broad spectrum of antiviral activity (including, for example, against other	519
paramyxoviruses such as metapneumovirus), sensitivity analyses are even more important.	520
Alternatively, stratification by the presence or absence of other respiratory virus coinfection	521
could be considered. In general, unlike influenza, RSV LRTI is not associated with a	522
concomitant or secondary bacterial respiratory tract infection. Therefore, FDA recommends the	523
exclusion of patients with potential concomitant bacterial respiratory tract infections requiring	524
treatment with antibacterial drugs.	525
526
For prophylaxis trials in infants and young children, all patients should have at least one risk	527
factor for severe RSV infection, such as prematurity, young chronological age at the onset of	528
RSV season, or a comorbid disease, as previously discussed. Patients with a history of	529
hypersensitivity to immunoglobulin preparations should be excluded from immunoprophylaxis	530
trials. Patients who receive another RSV prophylactic drug during the same RSV season should	531
also be excluded.	532
533
4. 	Randomization, Stratification, and Blinding	534
535
Clinical trials for prophylaxis and treatment indications should be randomized, double blind, and	536
controlled. Given the subjectivity of endpoints and the potential for variability in the course of	537
RSV disease, double blinding of treatment group assignment is important to reduce bias. In	538
cases where blinding is not considered feasible (e.g., use of an injectable placebo control in	539
pediatric studies of an injectable investigational formulation), additional measures should be	540
taken to minimize bias and ensure integrity of randomization.	541
542
Stratification factors to consider include known risk factors for moderate-to-severe RSV LRTI,	543
such as gestational and chronological age, comorbid conditions (e.g., CHD or CLD), and	544
geographic region. For treatment indications, stratification factors to consider include prior	545
prophylaxis with palivizumab in the same RSV season, severity of RSV disease, and coinfection	546
with other respiratory viruses.	547
548
5. 	Other Populations	549
550
Although the majority of severe RSV infections occur in young infants, several other populations	551
are at risk for severe RSV disease. HSCT patients of any age can have severe life-threatening	552
disease with RSV, and this population has a substantial need for RSV drugs. Depending on the	553
state of stem cell engraftment, HSCT patients may benefit from treatment of RSV infections	554
confined to the upper respiratory tract to reduce progression to the lower respiratory tract. The	555
severity of RSV disease may be dependent on the degree of immune suppression, with some	556
patients being at higher risk because of the nature of their transplants and the need for a high	557
degree of immune suppression. Other populations at risk for severe RSV disease include	558
patients with cystic fibrosis and older adults, especially those residing in long-term care	559
facilities.	560

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561
6. 	Use of Active Comparators	562
563
In randomized, controlled treatment trials in which a placebo is not considered appropriate,	564
active-controlled trials in which the comparator is an FDA-approved drug or considered the	565
standard of care for the indication may be appropriate (e.g., ribavirin for treatment of RSV LRTI	566
in bone marrow transplant patients). If a noninferiority trial design is considered, then a	567
noninferiority margin should be proposed, justified, and discussed with the DAVP because a	568
noninferiority trial may not always be considered appropriate.7 See section III.B.1.a., Treatment	569
of RSV LRTI, for further discussion about appropriate comparators.	570
571
An active control should be used in prophylaxis trials that include pediatric patients for whom	572
RSV prophylaxis is currently recommended. Placebo-controlled trials may be appropriate for	573
populations for which RSV prophylaxis is not recommended per local standard of care. Active-	574
controlled trials can be designed as superiority or noninferiority trials. Prevention of	575
hospitalization was used as the primary endpoint to support approval of palivizumab. A	576
noninferiority margin can be determined for prophylaxis studies in which palivizumab is the	577
comparator for the endpoint of hospitalization (or another agreed upon similar endpoint	578
demonstrated to be robust in a clinical trial) based on the treatment difference between	579
palivizumab and placebo for the same or similar population. Sponsors should discuss	580
construction of an appropriate noninferiority margin with the DAVP.	581
582
7. 	Efficacy Endpoints	583
584
Currently, efficacy endpoints have not been definitively established for clinical trials of RSV	585
treatment or prophylaxis; sponsors should work closely with the DAVP to identify reliable and	586
robust endpoints for treatment and prophylaxis of RSV disease of varying severity. For	587
treatment of RSV disease, a surrogate marker that reasonably predicts clinical response has not	588
been identified. Changes in RSV viral load may be informative for dose-ranging phase 2 PK/PD	589
analysis, but at this time, primary endpoints in phase 3 trials should be clinical outcome	590
measures. In addition, virologic surrogates are not expected to offer an advantage over clinical	591
endpoints because changes in both occur over the same time course.	592
593
Exploration of multiple secondary endpoints, including clinical and virological endpoints, is	594
strongly advised in phase 2 trials to show consistency of effect with the primary endpoint and to	595
inform selection of endpoints for pivotal phase 3 trials. Protocol submissions should include and	596
discuss prospectively the rationale for both primary and secondary endpoints.	597
598
a. 	Treatment	599
600
The primary efficacy endpoint should assess improvement in clinical signs and symptoms of	601
RSV disease. RSV disease is typically short in duration (less than 2 weeks in most children),	602
which allows for assessment of a primary clinical endpoint in a reasonable time frame in a	603
7 See the guidance for industry Non-Inferiority Clinical Trials to Establish Effectiveness.

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clinical trial setting, obviating the need for a surrogate measure of efficacy (El Saleeby, Bush, et	604
al. 2011; DeVincenzo, Whitley, et al. 2014).	605
606
The primary endpoint for treatment of RSV bronchiolitis could be time to a clinically	607
meaningful, defined level of improvement. Another option for the primary endpoint could be the	608
degree of improvement/resolution of signs and symptoms using a multipoint scale at a	609
prespecified time point. Instruments for sign and symptom measurement should be developed	610
and standardized to reliably and reproducibly measure signs and symptoms of RSV disease.	611
Relevant elements could include signs such as tachypnea, hypoxia, and chest wall retractions as	612
well as symptoms such as cough, wheezing, lethargy, and poor feeding. Some signs, such as	613
fever, tachypnea, and accessory muscle use, may resolve more quickly whereas other symptoms,	614
such as wheezing and cough, may persist and could be assessed separately as coprimary or	615
secondary endpoints. Sponsors should provide adequate justification for proposed endpoints and	616
the instruments used for sign and symptom assessment.	617
618
Patient-reported outcome (PRO) tools could be considered to assess symptoms in adults and	619
children who can reliably self-report. For patient populations that are unable to self-report (e.g.,	620
infants, young children, cognitively impaired), an observer-reported outcome (ObsRO) tool	621
could potentially be used to assess observable RSV-related signs, events, and behaviors.	622
Because no validated sign and symptom scoring system for RSV disease exists at this time,	623
sponsors should propose and provide justification for a standardized or well-studied instrument	624
for sign and symptom measurement and consult with FDA to develop well-defined and reliable	625
instruments. For further details regarding PRO and ObsRO development, refer to the guidance	626
for industry Patient-Reported Outcome Measures: Use in Medical Product Development to	627
Support Labeling Claims. Although not a regulatory requirement, the Drug Development Tools	628
Qualification Programs provide FDA consultation and advice on tools such as PRO and ObsRO	629
instruments that, once qualified, will be publicly available for use in multiple drug development	630
programs over time.8
631
632
Secondary and exploratory endpoints can include:	633
634
• 	Virologic assessments	635
• 	Prevention of hospitalization	636
• 	Prevention of disease progression, including prevention of intensive care unit admission	637
• 	Duration of supplemental oxygen use	638
• 	Duration of hospitalization	639
• 	Need for noninvasive positive-pressure ventilation or mechanical ventilation	640
• 	Duration of persistent symptoms such as wheezing and cough	641
642
Given that patients with RSV disease may be hospitalized and remain hospitalized for a variety	643
of reasons (e.g., respiratory compromise, the inability to take oral hydration or nutrition),	644
8 See the FDA web page Drug Development Tools Qualification Programs at
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/.

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interpretation of endpoints such as prevention of hospitalization or duration of hospitalization	645
may not always be straightforward.	646
647
b. 	Prophylaxis	648
649
In pediatric studies, the primary endpoint for prophylaxis studies should be the occurrence of	650
laboratory-confirmed RSV LRTI. In the past, prevention of RSV-related hospitalization was	651
used for approval of RSV immunoprophylactic drugs in pediatric patients; however, the utility of	652
prevention of RSV-related hospitalization as a primary endpoint has diminished as outpatient	653
management of RSV has improved and as patients with more serious RSV disease are managed	654
more often in the outpatient setting.	655
656
There has been considerable interest in the use of RSV prophylactic drugs to prevent wheezing	657
or asthma later in childhood. Assessment of long-term outcomes on symptoms such as wheezing	658
is not required for FDA marketing approval, but clinical trials could be designed to evaluate a	659
drug’s effect on wheezing or the development of asthma. Sponsors should be aware that the	660
more meaningful endpoint is prevention of asthma rather than reduction of long-term wheezing;	661
however, the Agency acknowledges that the studies evaluating prevention of asthma are longer	662
in duration and more difficult to conduct. Sponsors that plan to seek an indication for prevention	663
of long-term wheezing should discuss their plans with the Agency, because there may be unique	664
considerations with respect to trial design and endpoints that are beyond the scope of this	665
guidance.	666
667
In adult trials, possible endpoints for prophylaxis could include prevention of all symptomatic	668
respiratory infections, RSV LRTI (pneumonia), or progression of RSV upper respiratory tract	669
infection to LRTI.	670
671
8. 	Trial Procedures and Timing of Assessments	672
673
For treatment trials, intensive clinical assessments are important in the period shortly after	674
treatment initiation because the typical self-limited disease course in otherwise healthy children	675
may limit the ability to detect treatment effects at later time points. Clinical assessments should	676
be made at least three times daily. Virologic assessments should be performed by a central	677
laboratory using clinical samples obtained at presentation and at prespecified intervals	678
throughout the clinical course. These assessments should include quantitative RSV RT-PCR and	679
quantitative RSV culture. Clinical assessments can include serial measurement of respiratory	680
rate, oxygen saturation, work of breathing, and ability to maintain hydration through oral intake.	681
682
In prophylaxis trials, all patients who develop RSV bronchiolitis or pneumonia (i.e., prophylaxis	683
failures) should undergo virologic assessments performed by a central laboratory to confirm	684
RSV infection. These assessments should include quantitative RSV RT-PCR and quantitative	685
RSV culture. Because of the possibility of coinfection, diagnostic tests that detect multiple	686
respiratory viruses should be performed. Performance characteristics and descriptions of the	687
virologic assays should be provided in clinical trial protocols. Currently, an international	688
standard is not available for quantification of RSV RNA. Sponsors should include a readily	689
available reference for interstudy comparisons in their assays.	690

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691
Treatment trials should include at least 21 days of follow-up to detect symptom recurrence after	692
initial improvement, late-onset adverse events, or emergence of a resistant virus. Follow-up for	693
prophylaxis trials should continue for five half-lives of the drug to assess late-onset safety	694
events. Length of follow-up for treatment or prophylaxis studies may need to be longer	695
depending on the population (e.g., immunocompromised patients with prolonged viral shedding).	696
697
9. 	Statistical Considerations	698
699
Sponsors should provide a protocol with a statistical analysis plan for review and concurrence	700
before initiating patient enrollment. For treatment trials, the primary efficacy analyses should	701
focus on the population with laboratory-confirmed RSV infections, a baseline characteristic,	702
even if RSV infection is not confirmed until after baseline data are collected. Given the	703
likelihood that treatment decisions in clinical practice would be made before confirmation of	704
diagnosis, analyses of safety data should be based on all randomized patients. For prophylaxis	705
trials, the primary efficacy analysis should include all patients who are randomized and receive	706
at least one dose of assigned treatment during the trial.	707
708
In noninferiority trials, the choice of a noninferiority margin for statistical hypotheses should be	709
discussed and agreed upon with the DAVP before study initiation. Sponsors should determine a	710
reliable control treatment effect (M1) based on historical evidence of the quantitative	711
contribution of the active control. This contribution should be determined in trials evaluating a	712
similar population with similar length of follow-up as the proposed trial. In addition, the	713
noninferiority margin should be smaller than the M1 to preserve a clinically important effect	714
compared to an active control. For noninferiority testing, sponsors should employ two-sided, 95	715
percent confidence intervals adjusted for multiple comparisons or other appropriate testing	716
procedures. For additional information regarding noninferiority studies, see ICH E10 and the	717
guidance for industry Non-Inferiority Clinical Trials to Establish Effectiveness.	718
719
Sponsors should provide adequate details regarding the design, hypothesis, primary and	720
secondary analyses, control of family-wise type I error rate, and any assumptions for the	721
proposed sample size. If sponsors consider more than one primary endpoint, sponsors should	722
adjust the sample size at the planning stage to ensure sufficient power. FDA recommends a	723
stratified analysis when a trial is to be conducted in a heterogeneous population in which specific	724
characteristics might affect the magnitude of the treatment effect. Such specific characteristics	725
or factors should be prespecified and considered for stratified randomization. In these short-term	726
trials, sponsors should avoid censoring patients in the intent-to-treat infected population.	727
Missing data should be controlled and minimized, and the sponsor should have an explicit and	728
adequate plan to address issues relating to missing data.	729
730
10. 	Accelerated Approval (Subpart H) Considerations	731
732
Currently, no reasonably predictive surrogate endpoints are known for RSV disease in infants	733
and young children, and accelerated approval of RSV drugs is not a feasible drug development	734
pathway. In addition, it is not clear that surrogate endpoints would be useful in accelerating drug	735

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development because improvements in clinical symptoms can occur over the same time course	736
as changes in virologic measurements.	737
738
11. 	Risk-Benefit Considerations	739
740
RSV infection can result in a wide spectrum of illness in infants and young children from	741
asymptomatic infection to RSV bronchiolitis and pneumonia. Therefore, risk-benefit	742
considerations are extremely important for the development of RSV drugs for infants and young	743
children. Because RSV drug development will likely focus on studies in pediatric patients (21	744
CFR part 50, subpart D), risk-benefit assessments should be done for all drugs that are to be	745
tested. Depending on the patient population targeted (e.g., hospitalized patients with severe RSV	746
disease versus those with milder RSV disease), different degrees of risk may be reasonable.	747
However, any RSV drug targeting the entire infant population from birth to 12 months of age (or	748
up to 2 years of age in children with CLD or CHD) to prevent progression of RSV disease should	749
have a low risk profile to justify widespread use of the drug in children.	750
751
C. 	Other Considerations	752
753
1. 	Relevant Nonclinical Safety Considerations	754
755
General recommendations for supportive, nonclinical safety studies, including for the design and	756
timing, are addressed in other FDA and ICH guidances for industry. Small molecule drug	757
development is discussed in the ICH guidances for industry M3(R2) Nonclinical Safety Studies	758
for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals and	759
M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing	760
Authorization for Pharmaceuticals: Questions and Answers (R2). Recommendations for	761
biologically derived drugs are discussed in the ICH guidance for industry S6(R1) Preclinical	762
Safety Evaluation of Biotechnology-Derived Pharmaceuticals. Nonclinical considerations	763
specific to RSV drug development are discussed in this guidance.	764
765
In general, for small molecule drug development, FDA prefers that sponsors study the safety of	766
new pharmaceuticals initially in adult clinical trials. Nonclinical studies in two species of adult	767
animals (rodent and nonrodent) are commonly conducted to support the first-in-human trials in	768
healthy adults.9 If the small molecule pharmaceutical indication is intended primarily for a	769
pediatric population, FDA recommends that sponsors conduct juvenile animal toxicology studies	770
before initiation of pediatric studies to support the safety of the drug in the pediatric population.	771
Depending on the proposed duration of the exposure in the pediatric population, long-term	772
testing starting in juvenile animal toxicology studies may also be needed.	773
774
Drug development for biological products should employ a flexible and science-based approach.	775
If the biological product indication is intended primarily for a pediatric population, sponsors	776
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
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should consider feasibility and potential utility of a nonclinical safety evaluation in a juvenile	777
animal toxicology study.	778
779
2. 	PK/PD Considerations	780
781
a. 	PK measurement	782
783
The ability to measure drug exposures in the physiological compartment relevant to prophylaxis	784
or treatment of RSV is dependent on the route of administration and the mechanism of action.	785
For example, plasma concentrations may be easily quantifiable for drugs delivered via the oral or	786
parenteral routes, but may be less so for drugs that are inhaled or administered intranasally.	787
Additionally, plasma concentrations are more likely to reflect the systemic immunomodulatory	788
activity of prophylactic drugs, and local exposures may be more correlated with the antiviral	789
activity of drugs intended for treatment of RSV infection. Thus, for drugs that are inhaled or	790
delivered intranasally, drug concentrations in epithelial cells of the respiratory tract (estimated	791
from nasal wash, sputum, and/or bronchoalveolar lavage) should be measured to evaluate the	792
relationship of exposure and antiviral activity. Invasive procedures such as bronchoalveolar	793
lavage should be reserved for adult patients because the procedures are not done electively in	794
pediatrics.	795
796
Regardless of the route of administration, plasma drug concentrations should be collected	797
because the concentrations should be considered during safety assessments. FDA recognizes	798
that the collection of PK samples may be limited by the patient population under evaluation (e.g.,	799
pediatric patients); therefore, sample collection timelines should be designed to be maximally	800
informative.	801
802
b. 	PD measurement	803
804
The selection of robust and reproducible PD markers for antiviral activity against RSV is	805
hindered by an incomplete understanding of RSV disease. At present, FDA recommends the use	806
of changes in RSV virological measures and clinical symptoms related to RSV disease as	807
response metrics in exposure-response evaluations. Sponsors should select response metrics	808
based on biological plausibility, and relationships between selected response metrics and primary	809
efficacy endpoints should be characterized. During protocol development, the selected metrics	810
should be discussed and agreed upon with the Agency. Although information is limited, FDA	811
encourages sponsors to relate dose/exposure-response observations from short-term measures to	812
outcomes in phase 3 trials to inform dosing	813
814
The potential for clinical safety events to be exposure related should be assessed through	815
exposure-response analyses. Characterization of the relationship between drug exposure and	816
toxicity will help to delineate the upper limit of tolerable drug exposure and to estimate the	817
likelihood of an adverse event within a given exposure range.	818
819

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c. 	Modeling considerations	820
821
Sponsors should explore exposure-response relationships for efficacy and safety as early as	822
possible during clinical development (e.g., following adult phase 2 trial or trials).	823
Physiologically based pharmacokinetic analyses and/or population PK/PD analysis can be	824
utilized. Modeling should incorporate nonclinical antiviral activity, animal PK, safety, and PD	825
data as appropriate, as well as data from adult phase 1 and phase 2 trials, and physiological	826
difference between adults and infants to establish the initial dose to be evaluated in the first	827
infant study. This model should be refined on an ongoing basis as additional data become	828
available. It is not clear whether a model derived from adult and nonclinical data will be directly	829
applicable to the infant data. However, this model should be a starting point for continuous	830
model development. Sponsors should incorporate efficacy and safety data from placebo-	831
controlled arms into exposure-response models to allow for a clinically meaningful interpretation	832
of the safety and efficacy of the investigational drug. Sponsors should assess the influence of	833
demographic and baseline factors on models as appropriate. As with any drug development	834
program, knowledge of the exposure-response relationships for efficacy and safety will facilitate	835
dose selection in the primary patient population as well as for specific populations in which dose	836
adjustments may be needed.	837
838
3. 	Clinical Virology Considerations	839
840
a. 	RSV diagnostic assays for screening and events	841
842
Diagnosis of RSV infection should be confirmed by a central laboratory using an assay or assays	843
that are sensitive and specific for RSV A and RSV B. Performance data for the central	844
laboratory assay evaluating the geographically and temporally distinct isolates should be	845
submitted to the FDA for review. In addition, FDA recommends collecting any diagnostic	846
laboratory results from local clinical sites participating in trials, including identification of the	847
assay used.	848
849
Some RSV antiviral drugs might inhibit RSV diagnostic assays; for example, certain anti-RSV	850
monoclonal antibodies have been shown to compete with the antibodies used in specific	851
diagnostic assays, thereby reducing assay sensitivity (Deming, Patel, et al. 2013). Sponsors	852
should determine the effect of investigational drugs on the sensitivities of commercially available	853
diagnostic assays, particularly those used in clinical trials. These evaluations should be	854
performed using drug concentrations consistent with drug use.	855
856
b. 	Resistance analysis	857
858
Patients might fail RSV prophylaxis or treatment because of infection with a virus that is	859
resistant to the investigational drug. Resistant viruses may be transmitted (e.g., a patient is	860
infected with a virus that harbors polymorphisms that affect drug susceptibility) or selected (i.e.,	861
a resistant virus is selected within a patient after replicating in the presence of the drug).	862
Baseline and postfailure isolates from patients failing treatment should be genotypically	863
characterized and compared to determine if a drug-resistant virus is present and, if so, if the	864
resistant virus was present at baseline or selected within the patient. If genotypic analysis of	865

Contains Nonbinding Recommendations
Draft — Not for Implementation
21
RSV isolates identifies the emergence of a virus expressing novel substitutions not previously	866
analyzed during nonclinical resistance studies, the virus expressing those substitutions should be	867
phenotypically characterized. Sponsors should contact the DAVP to obtain the current format	868
for submission of resistance data. Sponsors proposing to use next generation sequencing should	869
consult with the DAVP early in the process.	870
871
4. 	Regulatory Considerations	872
873
Under the Pediatric Research Equity Act (Public Law 108-155) as amended by the Food and	874
Drug Administration Reauthorization Act (Public Law 115-52), sponsors must submit an initial	875
pediatric study plan (iPSP) to FDA no later than 60 days after the end-of-phase 2 meeting or at	876
such time as may be agreed upon between FDA and the sponsor.10 However, sponsors are	877
encouraged to begin discussions of their pediatric formulations and clinical development plans	878
early in drug development. The timing and content of the submission of an iPSP are described in	879
detail in the draft guidance for industry Pediatric Study Plans: Content of and Process for	880
Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans. As noted in	881
the guidance, the iPSP should include the entire pediatric age range.	882
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 FDA’s current thinking on this topic.

Contains Nonbinding Recommendations
Draft — Not for Implementation
22
REFERENCES	885
886
American Academy of Pediatrics, Committee on Infectious Diseases and Bronchiolitis	887
Guidelines Committee, 2014, Updated Guidance for Palivizumab Prophylaxis Among Infants	888
and Young Children at Increased Risk of Hospitalization for Respiratory Syncytial Virus	889
Infection, Pediatrics, 134(2):415–420.	890
891
Arnold JJ, Sharma SD, Feng JY, Ray AS, Smidansky ED, Kireeva ML, Cho A, Perry J, Vela JE,	892
Park Y, Xu Y, Tian Y, Babusis D, Barauskus O, Peterson BR, Gnatt A, Kashlev M, Zhong W,	893
and Cameron CE, 2012, Sensitivity of Mitochondrial Transcription and Resistance of RNA	894
Polymerase II Dependent Nuclear Transcription to Antiviral Ribonucleosides, PLoS Pathog,	895
8(11):e1003030.	896
897
Bockova J, O’Brien KL, Oski J, Croll J, Reid R, Weatherholtz RC, Santosham M, and Karron	898
RA, 2002, Respiratory Syncytial Virus Infection in Navajo and White Mountain Apache	899
Children, Pediatrics, 110(2 Pt 1):e20.	900
901
Deming DJ, Patel N, McCarthy MP, Mishra L, Shapiro AM, and Suzich JA, 2013, Potential for	902
Palivizumab Interference With Commercially Available Antibody-Antigen Based Respiratory	903
Syncytial Virus Diagnostic Assays, Pediatr Infec Dis J, 32(10):1144–1146.	904
905
DeVincenzo JP, Whitley RJ, Mackman RL, Scaglioni-Weinlich C, Harrison L, Farrell E,	906
McBride S, Lambkin-Williams R, Jordan R, Xin Y, Ramanathan S, O'Riordan T, Lewis SA, Li	907
X, Toback SL, Lin SL, and Chien JW, 2014, Oral GS-5806 Activity in a Respiratory Syncytial	908
Virus Challenge Study, N Engl J Med, 371(8):711–722.	909
910
El Saleeby CM, Bush AJ, Harrison LM, Aitken JA, and Devincenzo JP, 2011, Respiratory	911
Syncytial Virus Load, Viral Dynamics, and Disease Severity in Previously Healthy Naturally	912
Infected Children, J Infect Dis, 204(7):996–1002.	913
914
Englund J, 1994, Passive Protection Against Respiratory Syncytial Virus Disease in Infants: The	915
Role of Maternal Antibody, Pediatr Infect Dis J, 13:449–453.	916
917
Hall CB, McBride JT, Walsh EE, Bell DM, Gala CL, Hildreth S, Ten Eyck LG, and Hall WJ,	918
1983, Aerosolized Ribavirin Treatment of Infants With Respiratory Syncytial Virus Infection. A	919
Randomized Double-Blind Study, N Engl J Med, 308(24):1443–1447.	920
921
Marroquin LD, Hynes J, Dykens JA, Jamieson JD and Will Y, 2007, Circumventing the Crabtree	922
Effect: Replacing Media Glucose With Galactose Increases Susceptibility of HepG2 Cells to	923
Mitochondrial Toxicants, Toxicol Sci, 97(2):539–547.	924
925
Ralston SL, Lieberthal AS, Meissner HC, Alverson BK, et al., 2014, Clinical Practice Guideline:	926
The Diagnosis, Management, and Prevention of Bronchiolitis, Pediatrics, 134(5): e1474–e1502.	927
928
Randolph AG and Wang EL,1996, Ribavirin for Respiratory Syncytial Virus Lower Respiratory	929
Tract Infection, Arch of Pediatr Adolesc Med, 150(9):942–947.	930

Contains Nonbinding Recommendations
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23
931
Smee DF, Hurst BL, Evans WJ, Clyde N, Wright S, Peterson C, Jung KH, Day CW, 2017,	932
Evaluation of Cell Viability Dyes in Antiviral Assays with RNA Viruses That Exhibit Different	933
Cytopathogenic Properties, J Virol Methods, 246:51–57.	934
935
Taber LH, Knight V, Gilbert BE, McClung HW, Wilson SZ, Norton HJ, Thurson JM, Gordon	936
WH, Atmar RL, and Schlaudt WR, 1983, Ribavirin Aerosol Treatment of Bronchiolitis	937
Associated With Respiratory Syncytial Virus Infection in Infants, Pediatrics, 72(5):613–618.	938
939
Viswanathan M, King V, Bordley C, et al., 2003, Management of Bronchiolitis in Infants and	940
Children, Evidence Report/Technology Assessment No. 69: U.S. Dept of Health and Human	941
Services, Agency for Healthcare Research and Quality.	942