Guidance for Industry 
Influenza:  Developing Drugs 
for Treatment and/or 
Prophylaxis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

 
April 2011 

Clinical Antimicrobial 
 
   
Guidance for Industry 
Influenza:  Developing Drugs 
for Treatment and/or 
Prophylaxis 
 
 
 
Additional copies are available from: 

 
 
Office of Communications, Division  of Drug Information 
 
Center for Drug Evaluation  and Research 
 
Food and  Drug Administration 

10903 New Hampshire Ave., Bldg. 51, rm. 2201 
 
Silver Spring, MD   20993-0002 
 
Tel:  301-796-3400; Fax: 301-847-8714; E-mail:  druginfo@fda.hhs.gov 

http://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) 

 
April 2011 

Clinical Antimicrobial 
 
 
   
TABLE OF CONTENTS 

 
I.   INTRODUCTION............................................................................................................. 1 
 
II.   BACKGROUND ............................................................................................................... 2 
 
III.   DEVELOPMENT PROGRAM ....................................................................................... 4
  
A.   General Considerations .................................................................................................................4
  
1.  Nonclinical and Early Phase Clinical Development Considerations ..............................................4 
 
a.   Phase 2A: Challenge trials .......................................................................................................5
  
b.   Phase 2 dose-ranging trials .......................................................................................................6
  
2.  Drug Development Population.........................................................................................................7
  
3.  Efficacy Considerations ...................................................................................................................7
  
4.  Safety Considerations.......................................................................................................................9
  
B.   Specific Efficacy Considerations for Phase 3 Trials..................................................................10
  
1.  Trial Design....................................................................................................................................10
  
a.   Treatment trials: Acute uncomplicated influenza...................................................................10
  
b.   Treatment trials: Serious influenza in hospitalized patients...................................................10
  
c.   Prophylaxis trials.....................................................................................................................11
  
2.  Trial Population .............................................................................................................................12
  
3.  Entry Criteria .................................................................................................................................13
  
4.  Blinding ..........................................................................................................................................13
  
5.  Dose Selection and Route of Administration..................................................................................14 
 
6.  Efficacy Endpoints..........................................................................................................................14
  
a.   General considerations ............................................................................................................14
  
b.   Treatment of acute uncomplicated illness...............................................................................15 
 
c.   Treatment of seriously ill hospitalized patients.......................................................................16
  
d.   Prophylaxis .............................................................................................................................16
  
e.   Reduction in complications.....................................................................................................17
  
7.  Trial Procedures and Timing of Assessments ................................................................................17 
 
8.  Statistical Considerations for Phase 3 Trials.................................................................................19
  
a.   Treatment trials .......................................................................................................................20
  
b.   Prophylaxis trials ....................................................................................................................20
  
9.  Accelerated Approval (Subpart H) Considerations........................................................................22 
 
10.   Risk-Benefit Considerations ......................................................................................................23
  
C.   Other Considerations...................................................................................................................23
  
1.  Relevant Nonclinical Safety Considerations ..................................................................................23
  
2.  PK and PD Considerations ............................................................................................................23
  
a.   PK measurement .....................................................................................................................23
  
b.   PD measurement .....................................................................................................................24
  
c.   Modeling considerations .........................................................................................................25
  
3.  Labeling Considerations ................................................................................................................25
  
4.  Animal Rule (Subpart I) and Animal Model Considerations .........................................................25
  
5.  Emergency Access Considerations.................................................................................................26
  
a.   IND use ...................................................................................................................................26
  
b.   Emergency use authorization ..................................................................................................26
  
6.  Stockpiled Drug Products ..............................................................................................................27
  
7.  CMC Considerations......................................................................................................................28
  
REFERENCES............................................................................................................................ 29 

  Contains Nonbinding Recommendations 
1
 
Guidance for Industry  
Influenza:  Developing Drugs for  

Treatment and/or Prophylaxis 

 
 
 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this topic.  It 
does not create or confer any rights for or on any  person and does not operate to bind FDA or the public.  
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance.  
 
 
 
 
I.  INTRODUCTION  
 
The purpose of this guidance is to assist sponsors in the development of drugs for the treatment 
and/or prophylaxis of illness caused by influenza viruses A and B, including both seasonal and 
pandemic varieties.2  Specifically, this guidance addresses the Food and Drug Administrations 
(FDAs) current thinking regarding the overall development program and designs of clinical 
trials and nonclinical studies to support the development of influenza drug products.3  This 
guidance includes discussions on the following topics: 
 
	   Nonclinical development 
 
	   Early phases of clinical development  
 
	   Phase 3 protocol designs and endpoints for the treatment of both uncomplicated and 
serious influenza 
 
                                                 
1 This  guidance has been  prepared by the Division of  Antiviral Products in the Center for Drug Evaluation and  
Research (CDER) at the Food and Drug Administration.  
 
2 Influenza viruses are designated by type (i.e., A, B, or C), subtype (specifically for influenza A: H and N numbers 
based on 16  hemagglutinin and 9 neuraminidase antigens), and by strain  within types or subtypes.   During a typical  
annual influenza epidemic, influenza B and two principal subtypes  of influenza A (i.e., H3N2 and H1N1) circulate 
in varying  proportions.  New strains arise by ongoing antigenic drift within each  of these types or subtypes.  Many  
other influenza A subtypes occur in other host species, principally birds, and may cause occasional sporadic human 
infections.  Influenza  C has been reported  as a cause  of only sporadic mild disease and has not been a focus of either 
drug or vaccine development to date. 
 
3 For the purposes of this guidance, all references to drugs  include both human  drugs and therapeutic biological 
products  unless otherwise specified.  
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	   Protocol designs for prevention of symptomatic influenza 
 
	   The role of animal data in an influenza drug development program  
 
 	  Considerations relating to the potential for emergency use of influenza drugs, including 
advance development of protocols for further exploration and verification of drug effects 
under epidemic and pandemic conditions 
 
Sponsors considering development of antiviral drugs for the treatment or prophylaxis of disease 
with novel influenza strains, or in a pandemic influenza setting, are encouraged to consult this 
guidance and to communicate with the FDA through the pre-investigational new drug application 
(pre-IND) consultation program and frequently throughout drug development.  Proposals for fast 
track designation can be considered at any time during drug development, depending on 
appropriate fulfillment of the designated criteria.  
 
This guidance does not address drug development for the treatment and/or prophylaxis of 
influenza C. This guidance also does not address development of influenza vaccines or vaccine 
adjuvants. Inquiries regarding vaccines should be addressed to the Center for Biologics 
Evaluation and Research (CBER). 
 
This guidance does not contain discussion of the general issues of clinical trial design or 
statistical analysis. Those topics are addressed in the ICH guidances for industry E9  Statistical 
Principles for Clinical Trials and E10 Choice of Control Group and Related Issues in Clinical 
Trials.4    
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe the Agencys current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited. The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required. 
 
 
II.  BACKGROUND 
 
Effective vaccines are the central element in influenza control, but antiviral drugs are used for 
treatment of established influenza illness, and for postexposure or pre-exposure prophylaxis in 
selected situations. Antiviral drugs have been approved for treatment or prophylaxis of influenza 
A, influenza A and B, and influenza (not otherwise specified) based on trials in illness caused by 
circulating influenza virus strains. Approved antiviral drugs for influenza fall into two classes, 
neuraminidase inhibitors and the adamantanes. 
 
Influenza infections can produce a wide spectrum of clinical illness ranging from a self-limited 
febrile illness with respiratory symptoms to severe disease with complications sometimes 
                                                 
4  We  update  guidances periodically.  To make sure you  have the most recent version of a guidance, check the FDA  
guidance Web page  at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
2 
 Contains Nonbinding Recommendations 
resulting in hospitalization and death.  The severity of influenza depends on the virus strain and 
host, and is not always predictable at an individual level.  To date, antiviral drugs have shown the 
ability to modestly reduce symptoms in uncomplicated or otherwise self-limited illness.  
Currently, no antiviral drug has been shown to definitively reduce serious complications, 
hospitalization, or mortality in a randomized clinical trial.  Although this guidance addresses 
approaches to studying both self-limited and serious influenza, most regulatory experience 
involves trials in the treatment of uncomplicated illness (i.e., self-limited illness treated at home 
without secondary complications) and prophylaxis. 
 
Concerns about the possibility of pandemic spread of novel influenza strains have led to 
increased interest in influenza drug development;5 however, seasonal influenza remains a major 
public health concern. Because of their close relationship, seasonal and pandemic influenza are 
considered together in the discussions of regulatory approaches.  
 
Although terms such as avian influenza, epidemic influenza, and pandemic influenza have been 
used interchangeably in some scientific and media publications, they have important differences, 
as noted below: 
 
	   Avian influenza refers to any of a number of subtypes and strains that might be 
transmitted from birds to humans causing sporadic cases and clusters, and that might 
subsequently acquire capacity for rapid and widespread human-to-human transmission.   
 
 	  Epidemic influenza refers to a greater number of cases of influenza illness occurring in a 
community or region during a given period of time.   
 
 	  Pandemic influenza refers to a strain of predominantly avian, mammalian, or reassortant 
origin that has acquired capacity for transmission among humans and has emerged as a 
novel cause of widespread disease, dominating or replacing previously circulating 
subtypes (seasonal influenza) in human populations.  Although sporadic cases of novel 
strains raise concerns regarding a potential pandemic, it is difficult to predict which strain 
might emerge as a source for a pandemic.  In addition, substantial additional genetic 
change is likely as a novel strain progresses from sporadic to pandemic.  The difficulty in 
predicting the emergence of pandemic strains is illustrated by the recent antigenically 
novel reassortant strain of a previously circulating subtype (previously referred to as 
swine-origin influenza virus), which caused the first influenza pandemic of the 21st 
century.6  
 
 
                                                 
5 See documents and information at http://www.pandemicflu.gov. 
 
6 The 2009 pandemic strain of the H1N1 subtype differs antigenically from the H1N1 that has circulated in humans 
for decades; is reported to be  most closely related but not identical to H1N1 strains that have circulated in swine,  
containing  genes of swine, avian, and human origin; and  has not been detected in  nonhuman hosts before the 
emergence of human outbreaks in  2009.  The new strain also illustrates the lack  of predictable correspondence 
between subtype and antiviral susceptibility, having emerged  with a pattern of resistance mutations more similar to  
the seasonally circulating H3N2 than to the then most recent circulating H1N1 strains in  human populations. 
3 
 Contains Nonbinding Recommendations 
III.  DEVELOPMENT PROGRAM 
 
A.  General Considerations 
 
Influenza drug efficacy is evaluated in clinical trials conducted in the setting of circulating, 
naturally occurring influenza illness.  However, a drug effective in the treatment of seasonal 
influenza may not be effective or as effective in pandemic influenza or in sporadic cases caused 
by other novel strains. In addition, changes in seasonal strains, including emergence of 
resistance, can decrease drug effectiveness over time.  Thus, information on potential differences 
in drug responsiveness among strains or subtypes, including novel strains isolated from human 
infections, should be explored by generating and  assessing additional data from cell culture and 
animal studies, and by collecting and analyzing clinical data when feasible.  
 
Because of the public health implications of both epidemic and pandemic influenza, the variable 
nature of the disease, and limited therapeutic options and challenges in studying new options, 
novel approaches to the influenza drug development are of great interest.  Development 
pathways can be designed to provide information supporting access to investigational drugs if 
public health emergency arises during the development process.  Another important 
consideration is advance development of protocols for further exploration and verification of 
drug effects under changing epidemic and pandemic conditions.   
 
1.  Nonclinical and Early Phase Clinical Development Considerations  
 
Before initiating clinical trials, sponsors should investigate the mechanism of action and antiviral 
activity of the candidate drug using multiple types, subtypes, and strains of influenza virus 
derived from human clinical infections and from animals that can serve as sources for new 
clinical strains.  For a candidate drug with a mechanism other than direct antiviral effect, 
sponsors should conduct cell culture, biochemical, and genetic studies to support their animal 
toxicity studies (e.g., mouse knockout of the proposed target, receptor binding studies, and amino 
acid sequence homology analyses).  Different proposed mechanisms of action may affect the 
types of trials warranted to explore risk-benefit balance (e.g., potential effects of 
immunomodulators on disease processes in patients with pre-existing immunologic 
abnormalities). 
 
Candidate drugs should be assessed for antiviral activity in cell culture assays and, on the basis 
of those assay results, for in vivo activity in appropriate animal models of influenza infection.7   
Sponsors may need to assess the potential of their candidate drugs to enhance replication of other 
pathogens that mimic or complicate influenza, including other respiratory viruses and bacteria 
associated with similar illnesses or complications.  
 
Although not a regulatory requirement or replacement for clinical trials, cell culture and animal 
studies can: (1) make valuable contributions to clinical trial designs, including dosing 
                                                 
7 The National Institutes of Health (National Institute of Allergy and Infectious  Diseases, Division of  Microbiology  
and Infectious  Diseases, Virology Branch) has an antiviral drug screening program designed to  help identify 
potentially active antiviral drugs, including those to treat influenza.  Information about this  program and related 
activities can be accessed at http://www.niaid.nih.gov/topics/viral/Pages/Default.aspx. 
4 
 Contains Nonbinding Recommendations 
considerations and resistance monitoring plans; (2) assist in exploring the generalizability of  
clinical trial results; and (3) be used to: 
 
 	  Explore a candidate drugs activity against various strains of influenza including novel 
strains 
 	  Explore the effects of viral inoculum size of influenza exposure 
 	  Compare dosing regimens and routes of administration 
 	  Determine concentrations of the candidate drug at appropriate anatomic sites  
 	  Explore exposure-response relationships 
 	  Explore activity in immunocompromised hosts  
 	  Characterize viral resistance and transmissibility  
 	  Characterize treatment timing relative to the onset of clinically evident illness  
 
Proposals for animal studies should include supporting information on the selection, justification, 
and characterization of the animal model, and details of the natural history of disease in the 
model, as well as the proposed study design. When designing animal studies, sponsors should 
consider factors such as the relevance of the viral strain and need for adaptation to the host, the 
natural history of disease in the animal model, viral inoculum effects, dose and timing effects, 
and available information linking animal data to human exposure-response and outcomes.  
 
Virologic assessment and resistance monitoring are integral to the antiviral drug development for 
influenza. Sponsors should address virologic proposals together with their proposals for 
nonclinical studies and clinical trials throughout the development process, beginning with pre-
IND interactions with the FDA. 
 
a.  Phase 2A: Challenge trials 
 
After initial antiviral activity assessments and phase 1 human pharmacokinetic (PK) and 
tolerability trials, several sponsors have conducted challenge trials.  In challenge trials, healthy 
volunteers are administered an investigational antiviral drug either before (prophylaxis trials) or 
after (treatment trials) inoculation with the established challenge strain of influenza virus.  
Challenge strains are influenza viruses that produce a milder set of symptoms compared to 
naturally occurring influenza. Pharmacodynamic (PD) endpoints in challenge trials include 
clinical respiratory symptoms, nasal discharge weight, and quantitative measurements of viral 
shedding in nasal washes. Sponsors are encouraged to include assessments of resistance in their 
challenge trials. 
 
Challenge trials can provide useful exposure-response and safety information, as well as an 
opportunity to demonstrate pharmacological antiviral activity in humans under controlled 
conditions outside the influenza season. Data from challenge trials can contribute to dose 
selection for phase 2B and phase 3 trials, and provide the opportunity to explore the effects of 
different times of drug initiation relative to virus exposure.  However, challenge trials should not 
be considered efficacy trials that can be used to support marketing approval, because challenge 
strains typically produce a milder set of symptoms compared to naturally occurring influenza, 
and inoculation in challenge trials may differ from acquisition in naturally occurring infections 
(e.g., amount of inoculum in challenge trials could be larger or smaller at various mucosal sites 
5 
 Contains Nonbinding Recommendations 
compared to naturally occurring infections).  In addition, challenge trial results may not predict 
treatment outcomes for novel circulating influenza strains and pandemic strains because tissue 
distribution, viral replication, and host responses to novel strains can vary from those recognized 
in well-characterized challenge strains.   
 
Whether challenge trials are feasible is dependent on the availability of adequately safety-tested 
challenge strains and ethics considerations. Proposals for challenge trials should include 
documentation of the safety testing and biologics investigational new drug application (IND) 
status (in CBER) of the influenza challenge strains.  It is important for a sponsor wishing to use 
any new challenge strains to coordinate and consult with CBER staff reviewing the IND.  The 
use of novel strains of high or unknown pathogenicity is not an option for reasons of ethics, 
safety, and containment.   
 
Sponsors should provide dosing rationale for challenge trials on the basis of animal and human 
PK and tolerability data, cell culture EC  values (adjusted for protein binding), animal model 
50
PK/PD data, and any other relevant information.   
 
b.  Phase 2 dose-ranging trials 
 
The design of phase 2 dose-ranging trials depends on the type of population for phase 3 trials, as 
well as the phase 1 safety profile of the investigational drug.  We recommend that sponsors 
conduct phase 2 trials before designing phase 3 trials.  Proceeding directly to phase 3 from phase 
1 or phase 2A trials may fail to produce useful phase 3 data, especially if selection of doses and 
regimens are not scientifically justified.  Phase 2 dose-ranging trials usually are designed with 
adequate statistical power to detect differences in viral shedding (e.g., duration, quantitative 
differences from baseline), as well as differences in clinical symptoms that are included as 
secondary endpoints. Differences in virologic endpoints, together with numerical trends in 
clinical symptoms, are used to choose doses for further study in phase 3. 
 
It should be noted that clinical dose-response trials are one type of adequate and well-controlled 
trial that, if appropriate clinical endpoints in appropriate populations are measured, can 
contribute to substantial evidence of effectiveness (21 CFR 314.126).  In addition, exposure-
response trials and their analyses can provide support for approval of different doses, dosing 
regimens, or dosage forms.  Depending on the trial endpoints, exposure-response information 
can: 
 
   Help to connect cell culture antiviral activity (EC ) and exposure 
50
   Help to link animal and human findings  
   Provide guidance for designing clinical endpoint trials that use a rational dose range 
   Characterize activity against different influenza types and subtypes  
   Allow a risk-benefit analysis at different doses  
 
At present, it is not clear what PK exposure parameters or PD response parameters best predict 
anti-influenza efficacy outcomes.  However, duration of viral shedding in nasal washes is often 
measured, together with clinical symptoms such as nasal congestion, feverishness, sore throat, 
cough, aches, fatigue, headaches, and chills/sweats.  Typical influenza disease is restricted 
6 
 Contains Nonbinding Recommendations 
mostly to the respiratory tract and does not generally cause systemic viremia; however, there are 
occasional reports of isolation of viral RNA (e.g., A/H5N1) from other organ systems.  
Therefore, choice of virologic parameters for exposure-response analyses may depend on the 
influenza strain being studied. Sponsors are encouraged to discuss their choice of PD parameters 
with the FDA in a clinical development meeting during phase 1 or phase 2. 
 
For detailed information on trial design, see the guidance for industry Exposure-Response 
Relationships  Study Design, Data Analysis, and Regulatory Applications and Population 
Pharmacokinetics, and the ICH guidance for industry E4 Dose-Response Information to Support 
Drug Registration.   
 
2.  Drug Development Population 
 
Although influenza affects the entire population, phase 3 development plans can initially focus 
on treatment or prophylaxis of acute uncomplicated influenza in otherwise healthy individuals.  
However, we recommend that sponsors conduct trials in:  (1) persons at high risk of influenza 
complications, such as the elderly; (2) persons with underlying respiratory or cardiac disease; 
and (3) immunocompromised persons who may not experience the same benefit or safety profile 
as otherwise healthy adults. Such trials should be conducted as soon as appropriate data permit 
initiation of trials in these populations. 
 
Influenza occurs worldwide with differing seasonality but often with similar viral strains causing 
outbreaks across continents. Because the timing and magnitude of outbreaks in a given location 
may be difficult to predict, influenza drug development programs can involve diverse geographic 
locations. Protocols with a range of both northern and southern hemisphere sites increase 
efficiency of drug development by allowing collection of data through different influenza 
seasons. 
 
When sponsors rely on foreign clinical trial data  whether as part of multinational trials 
including the United States or as part of trials conducted entirely outside the United States  to 
support the marketing approval of their candidate drugs, they should supplement the foreign data 
with information about circulating influenza strains, patterns of clinical illness, trial population 
demographics, standards of medical care, and the use of other medical interventions in the 
countries where the trials were conducted. Sponsors should evaluate the relevance of foreign 
data under applicable FDA regulations, with considerations of trial conduct standards, trial 
population demographics, availability of sites for regulatory inspection, and applicability of 
disease manifestations and the standard medical care compared to that in the United States.  
Sponsors also can consult the guidance for industry Acceptance of Foreign Clinical Studies and 
the final rule Human Subject Protection; Foreign Clinical Studies Not Conducted Under an 
Investigational New Drug Application.8    
 
3.  Efficacy Considerations   
 
Efficacy trials for influenza treatment generally focus on symptom improvement in otherwise 
healthy persons with acute uncomplicated influenza.  However, large trials in otherwise healthy 
                                                 
8  See 73  FR 22800, April 28, 2008 (revising 21  CFR 312.120). 
7 
 Contains Nonbinding Recommendations 
populations may not be appropriate for some drugs if major limiting safety concerns have been 
identified in earlier development.  
 
In general, treatment and prophylaxis indications for influenza are different indications, and each 
indication should be supported by two adequate and well-controlled trials.  However, sometimes 
a single persuasive trial may be sufficient for each indication, depending on other supportive 
evidence.9  Two trials that differ in design parameters and populations usually are more useful 
than two identically designed trials or a single large trial.  For example, one treatment trial in 
adults and one treatment trial in children may be considered sufficient to support a treatment 
indication in adults and children.  Additional trials in special populations can be used to extend 
and/or further define indications. Data from trials for different influenza-related indications 
(e.g., treatment of acute uncomplicated illness, treatment of severe illness requiring 
hospitalization, postexposure prophylaxis, and seasonal prophylaxis) can provide supportive 
safety and efficacy information to the extent appropriate based on dosing, duration of treatment, 
and populations studied. 
 
With regard to indications for pandemic or avian influenza (as contrasted with seasonal 
influenza) or for a specific influenza subtype, molecular targets of antiviral drugs in general have 
not been shown to be subtype-specific. However, resistant strains can emerge in different 
subtypes and within the same subtype.  It may not be possible to predict antiviral drug efficacy 
against novel strains with little or no population immunity or strains with virulence factors that 
differ from the strains studied in clinical trials.  However, some drug effect is likely if the 
molecular target remains sufficiently similar.10  Information about strains circulating during a 
clinical trial is useful and should be collected and correlated with clinical outcomes where 
possible. 
 
Influenza development plans may be eligible for consideration under 21 CFR part 312, subpart E 
(Drugs Intended to Treat Life-Threatening and Severely-Debilitating Illnesses), fast track, or 
priority review if the specifics of the development plan justify such an approach.  However, 
accelerated approval using surrogate endpoints under 21 CFR part 314, subpart H,11 is not 
applicable to influenza drug development because clinical benefits are assessed over a short time 
period and no surrogate marker has been reliably identified as reasonably likely to predict 
important clinical outcomes.  For example, measurements of viral burden or shedding are not 
well standardized or characterized in relation to clinical outcomes, and clinical status generally 
can be measured at least as frequently and as rapidly as virologic status.  In addition, most 
                                                 
9 See the guidance for industry Providing Clinical Evidence of Effectiveness for Human  Drug and Biological 
Products for characteristics of a single adequate and well-controlled clinical trial that can contribute to a conclusion  
that such trial would be adequate to  support an effectiveness claim.  
 
10 Some proposals for drug  development may be based on strains predicted to interact with  a specifically designed 
molecule such as antisense oligonucleotides, small interfering RNAs, and  monoclonal antibodies.  Given the  
propensity of known strains to antigenic drift, it is difficult to ensure that a planned intervention can be designed to  
bind only  to  a single specific portion of a  predicted future pandemic  strain protein or  RNA.  Usually, development  is  
directed toward a conserved component of  both circulating and hypothesized future pandemic strains, and it may be 
prudent  to use mixtures of  different  antibodies or RNA segments to minimize escape mutations.    
 
11 See also  21 CFR part 601, subpart E, for the accelerated approval provisions for therapeutic biologics for serious  
or life-threatening illnesses. 
8 
 Contains Nonbinding Recommendations 
patients clear virus with or without treatment, and the magnitude and timing of treatment-related 
changes in viral shedding has not been clearly associated with clinically meaningful changes in 
disease resolution. Exploratory analyses of viral burden measurements at relevant sites and their 
relationship to adequately monitored and measured clinical outcomes may contribute to future 
understanding of the relationships between viral levels in clinical specimens and clinical 
outcome.   
 
Although using two or more antiviral drugs in combination might provide greater therapeutic 
benefit than using each drug alone in certain settings, such added value of combination therapy 
has yet to be established for influenza.  Combination therapy, particularly with drugs from  
different classes, can potentially result in synergistic or additive antiviral activity, or prevent or  
delay emergence of resistance.  Combining drugs also can be useful in cases where circulating 
viruses of different types or subtypes are known to harbor resistance-associated substitutions, 
and there are no readily available point-of-care tests capable of distinguishing between virus 
types or viruses with substitutions.  In this situation, the objective of the combination is to 
provide initial treatment for each of the major diagnostic possibilities, rather than to enhance 
treatment effect against a specific virus.   
 
However, combination treatment can result in increased toxicity and impractical dosing  
regimens.  In addition, hypothesized antiviral synergy might not be clinically meaningful.  
Therefore, trial designs should demonstrate the activity of each component of combination 
therapy (i.e., contribution of each component to the combination).12  Establishing the 
contribution of each component, generally using factorial designs, is important whether the 
proposed combination contains two or more antiviral drugs (e.g., a co-packaged combination, or 
a fixed-dose combination) or a drug and a therapeutic biological product.  Sponsors should 
consult 21 CFR 300.50 for specific regulatory considerations regarding fixed-dose combinations.  
 
4.  Safety Considerations 
 
It is important to develop a robust safety database from adequate and well-controlled human 
trials in appropriate populations because a wide variety of affected populations with a range of 
comorbidities could interact with both disease and treatment.  An application for initial approval 
of a new influenza drug for the treatment of uncomplicated influenza should include safety data 
from at least 1,500 patients at the dose and duration proposed for marketing.  A safety database 
larger than 1,500 patients may be needed if early safety signals have been identified in 
development.  Drugs that are intended to affect host cells or host responses, rather than directly 
affecting the virus, may need additional safety assessments (including special laboratory 
evaluations as appropriate for the agent) on more patients for unintended consequences of the 
host alterations. For new drugs showing important clinical benefit in serious influenza in 
hospitalized patients, an initial safety database of approximately 500 patients at the dose and 
duration proposed for treatment use may be sufficient for filing a marketing application for the 
treatment of serious influenza. 
                                                 
12 See the draft guidance for industry Codevelopment of Two or More Unmarketed Investigational Drugs for Use in  
Combination. When final, this  guidance will represent the  FDAs current thinking on this topic.  For the most recent 
version of a guidance, check the FDA guidance Web page  at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
9 
 Contains Nonbinding Recommendations 
 
Sponsors should provide a toxicity grading scheme  for clinical trials.  For trials of influenza 
prophylaxis or treatment of uncomplicated influenza, we recommend toxicity scales appropriate 
for use in healthy volunteers.13  For treatment of serious influenza or treatment of influenza in 
patients with underlying medical conditions, other toxicity grading scales can be used (e.g., those 
adopted by the AIDS Clinical Trials Group, National Cancer Institute, or the World Health 
Organization). 
 
B.  Specific Efficacy Considerations for Phase 3 Trials 
 
1.  Trial Design 
 
a.  Treatment trials:  Acute uncomplicated influenza 
 
Placebo-controlled trials are appropriate in settings and populations where the expected serious 
risk of nontreatment is small.14  For trials evaluating treatment of uncomplicated mild to 
moderate influenza, placebo-controlled rather than noninferiority designs should be used because 
the risks of receiving placebo are low, and the efficacy of available treatment is modest (1-day 
difference in time-to-symptom improvement), variable, and cannot be predicted well enough to 
support an adequate noninferiority margin.  The variable clinical course of influenza in any given 
season, as well as the potential for differences in pathogenicity and host immunity as new 
influenza strains emerge and change over time, also makes uncontrolled data or historical 
controls difficult to interpret and inadequate to support efficacy of investigational drugs.  
 
In addition to placebo-controlled trials, the following designs should be considered for acute 
uncomplicated influenza treatment trials:  (1) superiority trials with approved antivirals and/or 
symptomatic treatment as active controls in otherwise healthy adults or children; and (2) dose-
response (or concentration-response) trials where higher doses show significantly greater 
responses than lower doses. 
 
It is possible that future influenza drugs may be approved with large enough effect sizes relative 
to placebo that they may in turn be used as active controls in noninferiority treatment trials. 
 
b.  Treatment trials:  Serious influenza in hospitalized patients 
 
From a public health perspective, it is important to have treatments available for serious 
influenza in hospitalized patients.  However, there are few trials of antiviral drugs in this setting.  
In addition, because no trial has definitively demonstrated substantial clinical efficacy of an 
                                                 
13 See the guidance for industry Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in  
Preventive Vaccine Clinical Trials. 
 
14 Some public health authorities may not recommend routine treatment of influenza with currently approved 
antivirals because of concerns about risk-benefit, including the risk of resistance emergence. 
 
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antiviral drug in serious influenza or in hospitalized patients,15 determination of a noninferiority 
margin is not possible.  As a result, an active-controlled noninferiority trial is not possible.16    
 
Despite the lack of definitive randomized trials showing a specific magnitude of benefit of 
antivirals in the treatment of serious influenza, we acknowledge investigator concerns about 
randomizing hospitalized patients with serious influenza to placebo alone.  Consequently, 
sponsors can consider the following reasonable trial design alternatives in serious influenza:  (1) 
a randomized and blinded dose-response (or duration-response) trial, in which a significant dose 
response is demonstrated; and (2) a superiority add-on trial, in which the combination of an 
investigational drug plus a standard of care is shown to be superior to a standard of care (such as 
a drug approved for uncomplicated influenza used off-label for the treatment of serious 
hospitalized influenza). Showing efficacy differences in dose-response trials and superiority 
trials is challenging if all treatment arms are believed to have similar benefit.  Adequate 
frequency and intensity of patient assessments are important to maximize the likelihood of 
detecting potential, clinically relevant differences. 
 
Because outbreaks of influenza are unpredictable and enrollment of serious or hospitalized 
patients probably will be more difficult than enrollment of uncomplicated cases, sponsors should 
consider collaborating with clinical trial networks with a wide range of sites.  Trial design 
proposals should delineate how the proposed design (including sample size and power) will be  
able to detect an effect of the investigational drug on improving the patients clinical status.  
 
c.  Prophylaxis trials 
 
Prophylaxis trial designs include interventions in communities after documentation of circulating 
influenza, and household or institutional settings with documented exposure to a definite or  
clinically presumed case.  Both sample size and risk-benefit assessments of such trials may be 
affected by the assumed intensity of exposure.  For example, household or nursing home contacts 
may be at greater risk of disease than randomly recruited community dwellers.  In settings in 
which there are definite recommendations from  public health entities for drug prophylaxis (e.g., 
after onset of an outbreak within a nursing home), placebo controls will not be possible.  
 
In populations in which prophylaxis is not considered necessary, standard-of-care, placebo-
controlled trials can be considered.  In prophylaxis trials, the rates of symptomatic infection in 
placebo groups vary greatly depending on the season and population, and the number of illness 
outcomes in any treatment group may be small.  Vaccination status and changes in circulating 
viral strains also may effect the number of symptomatic cases observed.  The small number of 
                                                 
15 A limited number of  observational and case-control studies  have reported  various types of clinical benefit of 
antivirals for serious influenza; however, the margin of benefit was modest (both clinically and statistically).  There 
were also  questions about the reliability of the data because of potential biases when comparing treated and 
untreated groups.  Observational comparisons between presumed active treatments, or  between different times of 
treatment initiation, also  have  major risks of  bias, compromising the ability to derive reliable estimates of effect size 
from such comparisons.   
 
16 See the draft guidance for industry Non-Inferiority Clinical Trials. When  final, this guidance will represent the 
FDAs current thinking on this topic.  For the most recent version of a guidance, check the FDA guidance Web page  
at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
11 
 Contains Nonbinding Recommendations 
outcomes and resulting large confidence intervals in a noninferiority comparison can make it 
difficult to establish the effect of a new drug. For example, if two active drugs are compared and 
few or no cases of influenza illness are observed, this result can indicate similar effects of the 
two drugs, or lack of a true influenza outbreak, which would make it difficult to conclude the 
two drugs have similar effects.   
 
We consider the most straightforward household influenza prophylaxis trial design to be when:  
(1) all symptomatic infected index cases receive the same care (i.e., none is treated with any 
active drug, or all are treated with the same candidate drug, or all are treated with a specified 
alternative intervention); and (2) households are then randomized to the investigational drug or 
control (e.g., placebo), such that all members of the same household receive the same drug or 
control. This design does not provide information regarding whether treatment of the index case 
can itself decrease secondary transmission, or the potential interactions between the two 
interventions (e.g., reduction of prophylactic effect because of selection and shedding of resistant 
virus in the index case). To answer questions regarding influenza transmission, a four-arm  
factorial-design trial can be used in which index cases and household contacts are both 
randomized to treatment or placebo.  Alternatively, sponsors can consider two or more separate 
trials with differing designs depending on the importance of each of these questions in the 
context of the specific candidate drug. 
 
2.  Trial Population 
 
As mentioned previously, although influenza affects the entire population, phase 3 trials can 
initially focus on acute uncomplicated influenza in otherwise healthy individuals.  However, 
sponsors also should conduct trials enrolling persons at high risk of influenza complications, 
such as the elderly, individuals with underlying conditions such as respiratory or cardiac disease, 
and immunocompromised persons (e.g., HIV-infected patients, organ transplant recipients, or 
patients receiving cancer chemotherapy).  These patients may not experience the same benefit or 
safety profile from the candidate drug when compared with other patient populations.  It can be a 
challenge to design trials for patients at risk.  Possible trial design alternatives to placebo-
controlled designs include but are not limited to dose-response trials, active-controlled 
superiority trials, combination versus single therapy trials, and single-arm or active-controlled 
safety trials.    
 
In addition, trials in populations with little immunity to influenza and high or prolonged viral 
replication (e.g., young children and immunocompromised patients) may provide useful 
information about potential patterns of resistance emergence and relationships between the 
treatment dose or duration and clinical outcomes.  In trials of serious influenza, we encourage 
enrollment of patients with influenza-related complications, such as those needing intensive care 
support or mechanical ventilation. 
 
To fulfill the Pediatric Research Equity Act requirements and extend treatment and/or 
prophylaxis indications to pediatric age groups, sponsors need to conduct adequate and well-
controlled trials with clinical efficacy endpoints and complete safety evaluations.17  PK and 
safety trials will not be considered adequate to extend the indications to children, particularly 
                                                 
17 See the Pediatric Research Equity Act. 
12 
 Contains Nonbinding Recommendations 
those younger than 12 years of age.  Antiviral drug efficacy in children cannot be extrapolated 
from data generated from trials in adults because:  (1) prior exposure and immunity typically 
present in adults may affect influenza illness and response to treatment differently than in 
children; and (2) viral shedding may differ in pediatric and adult age groups.  
 
Sponsors can include adolescents in adult trials as appropriate, depending on an individual 
candidate drugs pharmacologic characteristics. 
 
3.  Entry Criteria  
 
For treatment trials, entry criteria should include documented influenza in the community and 
occurrence of influenza-like symptoms.  Laboratory confirmation generally is not available at the  
time treatment is initiated.   
 
Incorporation of a rapid test into the entry criteria might lead to a more reliably influenza-
infected population for analysis (as later confirmed by polymerase chain reaction (PCR), culture, 
or serologic titres). However, all of the currently available rapid tests have limitations, and the 
positive and negative predictive values of some rapid tests may not be much better than those of  
clinical screening criteria during a seasonal epidemic.  Novel influenza strains may have 
different test performance and/or different optimal sampling sites that may not be predictable 
from trials with previously circulating strains.  We recommend enrollment based upon clinical 
symptoms followed by confirmation with a sensitive and specific RT-PCR diagnostic assay at a 
central laboratory. 
 
Vaccination status can be an entry criteria or a stratification factor, and is likely to affect efficacy 
outcomes.  The likelihood of detecting treatment benefit in a highly vaccinated population may 
be decreased because the incidence and severity of illness may be reduced.  However, such 
likelihood may be increased if pre-existing immunity and drug treatment are additive or 
synergistic, as some trials suggest.  Antiviral drugs might theoretically have deleterious effects 
on response to a live-virus influenza vaccine if they are administered in the same time period as 
the vaccine and inhibit replication of the vaccine virus.  Therefore, individuals who have recently 
received a live-virus influenza vaccine generally should be excluded from participation.  Drug 
effects in response to inactivated vaccine are less likely.  Documentation of vaccination status 
and performance of appropriate statistical interaction analyses are important parts of trial design, 
conduct, and interpretation. 
 
For prophylaxis trials, entry criteria generally should be broad and reflect the population 
intended for use. Most trials will be conducted in otherwise healthy adults.  Trials can be 
designed to look at families, college students, or perhaps individuals with underlying health 
conditions in institutionalized settings (e.g., nursing homes).  
 
4.  Blinding 
 
Double-blinding of treatments is important, given the subjectivity of endpoints and the potential 
for confusion between the natural variability of influenza and the drug effects (either beneficial  
or adverse). 
13 
 Contains Nonbinding Recommendations 
 
5.  Dose Selection and Route of Administration 
 
Animal studies, challenge trials, and dose-ranging trials in naturally occurring influenza disease 
can all contribute to dose selection for pivotal clinical trials.  Exposure-response relationships 
can be assessed in all of these settings. PD parameters, such as those relating to viral clearance, 
also can be explored. As  previously noted, we strongly recommend that sponsors conduct 
adequate phase 2 trials before designing the phase 3 trials.   
 
For some drugs, more than one route of administration can be considered, which may result in 
different dosing, safety, and efficacy issues. For example, an oral form may be desirable for 
uncomplicated influenza, whereas an intravenous formulation may be more desirable for 
seriously ill patients who may not be able to take oral formulations.  For inhalational routes, it 
can be challenging to determine appropriate dosing for clinical trials based on nonclinical data.  
In addition, if a novel strain is associated with viral replication in a broader range of organ 
systems than the usual seasonal influenza, an inhalational route may be insufficient to have an 
antiviral effect in organs other than the lungs and respiratory tract.  The safety of drugs delivered 
by inhalational routes should be evaluated in subjects with pre-existing pulmonary disease, with 
appropriate safety precautions and monitoring, because individuals with pulmonary disease may 
be at highest risk for both influenza complications and adverse reactions caused by inhalational 
drugs. 
 
The use of an antiviral drug with an inhalational device for delivery is subject to the FDA 
regulations at 21 CFR part 3, which provide procedures for determining which FDA center has 
primary jurisdiction for a combination product with components potentially subject to review in 
different centers.  Generally, combination products are regulated through the Center for Drug 
Evaluation and Research (CDER) because the drug component represents the primary 
mechanism of action of the product.  Drug review can involve consultation and collaboration 
across divisions or centers depending on the specific attributes of each component.  The sponsor 
of a proposed combination product should ensure that adequate information is provided to the 
FDA about the device as well as the drug in such a combination, including any proprietary 
information that may be needed for review.  If there are questions about which center has 
primary jurisdiction, a determination can be requested at the time of initiating interactions with 
the FDA.18   
 
6.  Efficacy Endpoints 
 
a.  General considerations  
 
Efficacy endpoints can involve combinations of objective measurements, evaluations by health 
care professionals, and patient-reported symptoms.  Efficacy endpoints have not been 
definitively standardized for all types of influenza trials; however, duration of defined influenza 
symptoms has been used in registrational trials of acute uncomplicated influenza.  There have 
been recent advances in endpoint assessment using patient-reported components of outcome  
                                                 
18 For more information, contact the Office of Combination Products 
(http://www.fda.gov/CombinationProducts/default.htm).  
14 
 Contains Nonbinding Recommendations 
measurements.19  Because of the variability of influenza illness and drug effects in previous 
trials, most clinical trials warrant examination of multiple secondary endpoints to show  
consistency of effect with the primary endpoint.  Rationale for both primary and secondary 
endpoints should be included in protocol submissions and discussed prospectively with the FDA.    
 
For treatment trials, virologic measurements are important secondary endpoints and can be used 
as components of entry criteria or evaluability.  Currently, we do not consider virologic 
endpoints to be appropriate primary endpoints in phase 3 treatment trials because:  (1) there is no 
established predictive relationship between magnitude and timing of viral reductions and extent 
of clinical benefit of how a patient feels, functions, or survives; (2) optimal sampling site, 
methods including collection procedures, and assays for clinically relevant virologic 
measurements have not been established; and (3) available data suggest substantial variability in 
results and conclusions using different methods for collecting and analyzing virologic data.  
 
In addition, unlike trials in HIV and hepatitis C virus, influenza clinical outcomes occur in the 
same time frame as virologic changes.  Therefore, using virologic endpoints does not shorten 
trial duration. Previous influenza trials do not suggest that virologic endpoints would provide a 
quicker or easier way to distinguish between therapies than direct measurements of clinical  
outcome.  Thus, even if more evidence can be collected regarding the predictive value of 
virologic measurements, such measurements would not necessarily reduce the trial size or 
duration, although they could further contribute to secondary analyses. 
 
Viral assays also contribute to the laboratory confirmation of endpoints in prophylaxis trials.  
Identification of specific viral subtypes and strains also can be valuable for secondary analyses.  
Sponsors should explore the development of methodology for quantitative cultures and 
quantitative RT-PCR at relevant sites, and for assessment of relationships between viral burden 
(including asymptomatic shedding) and secondary transmission.  Sponsors should also provide 
assay performance data with currently circulating strains to support the use of the proposed 
assays in their trials. 
 
In trials of acute uncomplicated influenza, concomitant use of symptomatic relief medications 
may make the endpoint evaluation more difficult.  Confounding caused by concomitant 
medicines may be mitigated if protocols are standardized to measure their administration.  
Alternatively, a standardized regimen of symptom relief medication (e.g., acetaminophen) may 
be used as an active comparator to an influenza antiviral drug in a superiority design trial.   
 
If sponsors propose claims of reduction in complications, objective criteria should be delineated 
and justified prospectively. Information on the specifics of diagnosis and management should be 
collected in the protocol.    
 
b.  Treatment of acute uncomplicated illness 
 
The primary endpoint in treatment trials in adults for acute uncomplicated influenza should be 
the time to a pre-defined level of symptom improvement.  Components of the primary endpoint 
                                                 
19 See the guidance for industry Patient-Reported Outcome Measures:  Use in Medical Product Development to 
Support Labeling Claims. 
15 
 Contains Nonbinding Recommendations 
should include fever with a constellation of symptoms (e.g., cough, coryza, headache, body 
aches, sore throat). This clinical symptom endpoint is not considered a surrogate endpoint 
because it measures clinically relevant symptoms associated with influenza.  For treatment of 
acute illness in otherwise healthy individuals, demonstrating reductions in secondary 
complications or mortality is not necessary for an antiviral to be considered clinically useful.  
Secondary clinical endpoints should be time to return to normal activity, and time to resolution 
of fever, and/or other individual symptoms included in the primary endpoint.  The emergence of 
drug resistance is an important tertiary endpoint in all influenza trials. 
 
Sponsors should provide justification for a standardized and/or well-accepted instrument for 
symptom measurement.  We discourage adding scores for different symptom types into an 
aggregate score or area under the curve of symptoms.  We consider these analyses exploratory 
because it is difficult to equate the units of severity of different symptoms.  
 
The population for both the primary analysis and additional analyses should include all subjects 
with confirmed influenza (i.e., intent-to-treat (ITT) infected population).  Exploratory analyses of 
on-treatment or per-protocol populations may be used to identify problems with dosing 
approaches or instructions. 
 
c.  Treatment of seriously ill hospitalized patients 
 
For seriously ill influenza patients requiring hospitalization, a primary endpoint should include 
clinical signs and symptoms, duration of hospitalization, time to normalization of vital signs and 
oxygenation, requirements for supplemental oxygen or assisted ventilation, and mortality.  
Choice of endpoint may depend on the clinical setting and/or viral strains.  A single best 
endpoint has not been identified in seriously ill hospitalized patients, and clinical trial proposals 
should be provided for advance discussion. Sponsors are encouraged to provide evidence for the 
ability of their proposed endpoint to directly measure how a patient feels, functions, or survives, 
taking into account all relevant documentation from literature sources and clinical trials.  Such 
endpoint is intended to demonstrate whether the candidate drug produces a more rapid and/or 
more complete improvement in the condition of the patient compared to the control.  Further 
developmental work to evaluate the most relevant clinical endpoint for assessing benefit in trials 
of serious influenza treatment is needed and strongly encouraged. 
 
d.  Prophylaxis 
 
The primary endpoint for prophylaxis trials should be the occurrence of symptomatic, 
laboratory-confirmed influenza.  Symptom diaries, along with serology and targeted cultures or 
nucleic acid amplification tests (NAATs), have been used to identify laboratory-confirmed cases 
of symptomatic influenza.  Additional analysis of all subjects with influenza-like symptoms  
(with or without laboratory confirmation) can be a useful secondary endpoint.  However, such 
approach may include noninfluenza illnesses with symptoms similar to influenza that are not 
susceptible to anti-influenza drugs, and would presumably reduce the effect size.  
 
We recommend a secondary analysis that compares the prophylactic effect of all subjects (both 
symptomatic and asymptomatic) with laboratory evidence of influenza infection.  However, the 
16 
 Contains Nonbinding Recommendations 
clinical benefit of preventing asymptomatic infection is unclear, because the goal of influenza 
prophylaxis is to prevent symptomatic illness, and not just asymptomatic laboratory-identified 
seroconversion. On the one hand, it may be preferable to avoid infection altogether because 
asymptomatically infected persons might shed and transmit virus despite the presence of the 
prophylactic drug. On the other hand, asymptomatic infection may offer protection against 
illness if a new exposure occurs after subjects have stopped taking a prophylactic drug.  
 
In addition to the primary objective of preventing symptomatic influenza illness, there is interest 
in ascertaining whether disease is milder in persons who develop it while receiving prophylaxis 
compared to persons not receiving prophylaxis.  This outcome may be difficult to assess in most 
prophylaxis trials because of the relatively low numbers of breakthrough cases among 
individuals receiving active antiviral drugs.  However, if appropriate collection of symptom  
information is prospectively included during protocol planning, such severity-of-illness 
comparison can be a useful analysis for potentially supporting additional statements in product 
labeling. 
 
e.  Reduction in complications 
 
Findings and symptoms that are part of influenza illness should not be considered separate 
complications if they are part of a multicomponent principal endpoint.  Bacterial infection 
complications should meet pre-defined criteria according to appropriate expert guidelines.  For 
example, a clinical diagnosis of bronchitis may be part of the clinical spectrum of influenza 
itself, and may not meet the criteria for a secondary bacterial infection.  We encourage sponsors 
to propose prospectively definitions of potential serious outcomes for secondary analysis, 
including those outcomes expected to occur with low frequency and therefore not likely to have 
sufficient event numbers for primary analysis.  Methods of diagnosis and confirmation of 
secondary infections should be described in detail in the protocol and be consistent across all 
trial sites. Diagnoses of secondary complications should be confirmed by objective clinical, 
laboratory, and medical imaging findings as appropriate.  In the absence of such objective 
confirmation, labeling statements regarding efficacy claims for the prevention of secondary 
complications are unlikely. 
 
7.  Trial Procedures and Timing of Assessments 
 
Intensive clinical assessment is important in the period shortly after treatment initiation in 
treatment trials and presumed exposure in prophylaxis trials.  The typical self-limited disease 
course may limit the ability to detect treatment effects at later time  points.  Prophylaxis and 
treatment trials should include sufficiently long follow-up to detect symptom recurrence after 
temporary improvement, late adverse events, or emergence of resistant virus.  Protocols should 
include frequent self-assessments (e.g., use of diary cards), along with observer assessments at 
less frequent intervals or as triggered by self-assessment results.  Self-assessments should 
continue until resolution of all clinical signs and symptoms.  For trials in hospitalized patients, 
some aspects of clinical assessment may be suitable for frequent measurement, and/or may be 
routinely recorded in hospital medical records and available for analysis, especially during the 
initial period of acute illness.  Self-reporting of symptoms may become more important in 
patients who are improving but still symptomatic.  
17 
 Contains Nonbinding Recommendations 
 
Available in vitro diagnostic tests for influenza, ranging from research laboratory procedures to 
marketed test kits, use multiple methods, and require anywhere from minutes to days to 
complete.  Marketed test kits for influenza are regulated by the Center for Devices and 
Radiological Health (CDRH), and include several rapid tests designed to detect viral antigens or 
enzyme activity within 30 minutes.20  The ability to obtain specific types of diagnostic 
specimens, and to achieve the desired test sensitivity and specificity in the setting of infection, 
may vary with factors such as severity of disease, patient age, treatment timing, collection 
technique, and characteristics of novel viral strains, such as principal anatomic distribution and 
sites of viral replication. Currently, FDA-cleared rapid tests for influenza can be labeled as 
detecting influenza A, detecting influenza A and B without distinguishing between the two types, 
or detecting and distinguishing between influenza A and B.  One subtype-specific NAAT for 
H5N1 has been recently cleared. Tests labeled for influenza A (or A and B) may detect a 
number of subtypes in analytic testing.  However, clinical experience is limited to the subtypes 
and strains circulating at the time when trials supporting the FDA clearance of the tests were 
conducted. 
 
Although results would likely not be available at trial entry, we recommend inclusion of a 
sensitive and specific assay (e.g., real-time RT-PCR assay) for laboratory confirmation of 
influenza infection to assist in defining the infected population for trial analyses in influenza 
treatment trials. 
 
We consider diagnostic and monitoring assays that are used in a clinical trial but have not been 
cleared by the FDA to be investigational. Drug sponsors should provide sufficient information 
on the methodology and performance of such assays to allow the FDA to evaluate the 
appropriateness of the assays for their intended use. Use of an investigational assay in a clinical 
trial does not constitute FDA clearance or endorsement of the assay.  If a diagnostic assay 
proposed for use in a clinical trial has not been previously cleared by the FDA but eventually 
may be developed for commercial distribution, the sponsor should consider early discussions 
with CDRH as well as CDER to facilitate collaborative or consultative review and comment as 
appropriate. 
 
In trials designed to evaluate the efficacy of an anti-influenza drug for treatment, viral influenza 
cultures (i.e., nose and/or throat swabs or nasal wash) should be performed at baseline (before 
dosing) and at appropriate intervals during and after drug treatment.  Duration of viral shedding 
is a valuable secondary endpoint but may be difficult to determine if cultures are performed 
infrequently. Measurement of anti-influenza antibodies should be performed at baseline and 
                                                 
20 CDRH regulates in  vitro diagnostic tests for influenza and has published the following guidances for industry  and 
FDA staff on its Web site at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/default.htm:   In 
Vitro Diagnostic Devices to Detect Influenza  A Viruses:  Labeling and Regulatory Path and Establishing the 
Performance Characteristics of  In  Vitro Diagnostic Devices for the Detection or  Detection and Differentiation of  
Influenza Viruses on  development of influenza diagnostics (when  final, this guidance will represent the FDAs 
current thinking  on this topic), and a Laboratory Safety Tip,  Cautions in  Using Rapid Tests for Detecting  Influenza  
A Viruses  
(http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/TipsandArticlesonDeviceSafety/ucm109356.htm), 
that discusses cautions in the use of rapid influenza tests that can detect influenza virus antigens or viral enzyme  
activity within  30 minutes. 
18 
 Contains Nonbinding Recommendations 
during follow-up, preferably about 4 weeks after diagnosis.  Serology should use standardized 
methodology, and supporting information for the assay should be provided in advance.  
Seroconversion response to influenza antigens is assessed as an increase by a factor of 4 or 
greater to assist in confirming influenza diagnosis in treatment trials, and as part of the outcome  
definition of laboratory-confirmed symptomatic influenza in prophylaxis trials.  Therefore, it is 
important to assess whether an antiviral drug interferes with antibody response once infection is 
established in treatment trials and to evaluate the extent of effects on seroconversion in 
prophylaxis trials. 
 
Subtyping and genotyping may be important for exploration of relationships between viral type 
and treatment, and for identification of sources of viral transmission in trials of prophylaxis.  
Baseline susceptibility and emergence of resistance to the trial drug should be examined in 
clinical trials, regardless of trial designs.  If standardized and generally accepted susceptibility 
testing methods are not available, samples should be retained for future testing until the trial has 
been completed and data have been analyzed.  In some instances, more than one approach to 
susceptibility testing may be warranted.  For example, enzyme inhibition assays may be useful in 
screening samples but may generate different results from virus yield assays; yet both may be 
important for the assessment of drug resistance.  Recent trials have shown higher rates of 
resistance to influenza drugs when a clonal analysis is employed.  We recommend that resistance 
be evaluated early in development to better inform phase 3 protocol design.  Sponsors should 
consult existing guidance on virology studies and submission of resistance data for aspects 
relevant to influenza.21    
 
Interactions between vaccines and antiviral drugs may warrant consideration in some trial 
designs. Timing of serum sample collections to assess seroconversion should be considered to 
distinguish between antibody responses to vaccine and infection-related seroconversion as a 
diagnostic confirmation.    
 
Sponsors should provide detailed viral resistance monitoring plans that describe proposed 
analyses, sample collection timing, assay characteristics with different influenza types and 
subtypes, and assay methodologies.  Such plans should be provided to the FDA for review early 
in development, and updates to the plans should be discussed at appropriate intervals during 
development.  The issue of relative fitness of resistant viruses should be approached with great 
caution, given the complexity of potential determinants of infectivity and virulence, and the 
potential for multiple mutations with diverse and sometimes compensatory consequences. 
 
8.  Statistical Considerations for Phase 3 Trials 
 
Sponsors should provide a protocol with a statistical analysis plan for review for FDA 
concurrence before subject enrollment.   
 
                                                 
21 See the guidance for industry Antiviral Product Development  Conducting and Submitting Virology Studies to 
the Agency and its attachment  Guidance for Submitting  Influenza Resistance Data. 
19 
 Contains Nonbinding Recommendations 
a.  Treatment trials 
 
The primary efficacy analyses should focus on the population with laboratory-confirmed 
influenza, a baseline characteristic even if it is not defined until after baseline data are collected.  
The primary endpoint in treatment trials in adults for acute uncomplicated influenza illness 
should be the time to a pre-defined level of symptom improvement.  Analyses of safety data 
should be based on all randomized subjects given the likelihood that treatment decisions in 
clinical practice would be made before confirmation of diagnosis. 
 
The unit of randomization and analysis in such trials is the individual trial subject.  We  
recommend stratification by time since onset of symptoms when there is a sufficiently wide 
window for enrollment to make this stratification meaningful.  Consideration of other possible 
stratification variables also can be useful when a trial is to be conducted in a heterogeneous 
population in which specific characteristics such as viral strain, smoking status, location, or the 
use of nonprescription symptom relief medication or other concomitant treatments might affect 
the natural history of illness and/or the magnitude of treatment effect. 
 
Sponsors should avoid censoring subjects in the ITT infected population in these short-term  
trials. There should be an explicit and adequate plan to address issues relating to missing data. 
 
b.  Prophylaxis trials 
 
In prophylaxis trials, the primary endpoint should be the occurrence of symptomatic, laboratory-
confirmed influenza.   
 
Examples of populations that can be enrolled in prophylaxis trials, each with its own design and 
analysis considerations, include households, communities of healthy adults, and nursing homes.   
 
	   Households.  Households with multiple members in the appropriate age categories 
should be identified and screened in advance.  When an index case is reported in a 
screened household, that household should be randomized to one treatment arm. There 
are three possible designs, as follows:   
 
1.	   Index cases are untreated and all contacts in a household are randomized to the same  
treatment, either placebo or candidate drug  
 
2. 	  Index cases are treated and all contacts in a household are randomized to different 
treatments, which could be placebo or candidate drug  
 
3.	   Factorial trials with four arms are conducted that include all four combinations of 
index cases (treated or untreated) and contact cases (treated or untreated):  
 
   Index treated and contacts given prophylaxis (with candidate drug) 

   Index treated and contacts given placebo 

   Index untreated and contacts given prophylaxis (with candidate drug) 

   Index untreated and contacts given placebo 

20 
 Contains Nonbinding Recommendations 
 
The second design is a less powerful test of prophylaxis than the first design if treating 
the index case reduces the risk of influenza infection to the contact cases.  The third 
design is recommended if one wishes to assess the benefit of:  (1) index case treatment on 
contact case risk; and (2) contact case prophylaxis. 
 
In household trials, the entire household is both the randomized unit and the unit of 
analysis. The primary efficacy analysis should compare the treatment groups for the 
percentage of households in which at least one randomized contact case developed 
symptomatic, laboratory-confirmed influenza.  In other words, if one contact case in the 
household becomes symptomatically infected, the household is counted as infected.  If 
none of the contact cases becomes infected, the household is considered not infected.  
Secondary analyses also can compare the percentage of contact cases that had 
symptomatic, laboratory-confirmed influenza in the active and placebo treatment groups.  
 
Designs in which different contact cases in the same household receive different 
regimens raise concerns of drug sharing and intrahousehold correlation.  Analysis using 
individual contact cases as the unit of analysis also may cause similar problems.  
Stratification on the size of household can be used, but is not expected to produce any 
consequential increase in power. 
 
 	  Communities of healthy adults.  For community trials with healthy adults (e.g., trials 
conducted in college campuses), subjects should be screened at the beginning of the flu 
season and randomized to control or test prophylaxis arms when there is occurrence of a 
predefined epidemiological signal that an influenza epidemic is underway in the target 
community, or in a larger community (e.g., the county where the college campus is 
located). 
 
 	  Nursing homes.  For trials in nursing homes, screening, randomization, and analysis 
should be similar to those for trials in communities of healthy adults.  Nursing home trials  
should involve more careful definition and monitoring of clinical endpoints because 
subjects may lack mental acuity for self-assessment and staff need to monitor many 
aspects of all subjects health. These concerns should be considered in treatment trials in 
nursing homes as well. 
 
In prophylaxis trials in nursing homes and other community dwellings, the individual 
trial subject is both the unit of randomization and the unit of analysis.   
 
Statistical power in prophylaxis trials depends on the number of protocol-defined endpoint 
outcomes (i.e., symptomatic, laboratory-confirmed infection) and the effect size of the 
intervention, rather than the number of subjects enrolled.  Therefore, the sample size of  
prophylaxis trials should be based on the number of such outcomes expected and a conservative 
estimate of effect size.  Because incidence of influenza varies unpredictably from year to year, 
the number of subjects in a community prophylaxis trial during one flu season may yield fewer 
than the expected number of influenza illnesses.  We recommend monitoring total number of 
influenza cases to determine whether it is lower than expected.  It is appropriate to continue the 
21 
 Contains Nonbinding Recommendations 
trial into a second flu season if influenza attack rates are low, even if such continuation was not 
initially specified in the protocol.  There should be no unblinding of results at the end of the first 
season if the total number of influenza illnesses is still inadequate at that point.   
 
For prophylaxis trials, principal analyses and power calculations can be based on the odds ratio 
or relative risk comparing the prophylaxis failures (i.e., symptomatic, laboratory-confirmed 
influenza) between the treatment arms.  Because failures tend to be few in the active prophylaxis 
arms, exact statistical procedures should be used instead of normal approximations for 
inferences. 
 
Minimizing missing data is important in prophylaxis trials that have a small number of treatment 
outcomes.  Investigators should be diligent in obtaining the final status of subjects either on or 
off the assigned treatment, regardless of whether they are in the trial or have been terminated 
from the trial.  If a subject does not come back for evaluation after the sponsor has exhausted all 
reasonable means to persuade the subject to do so, the following information should be collected 
and documented:  the subjects status (e.g., whether alive or not), a description by the subject and 
his or her contacts of the subjects flu symptoms and adverse events, and the general well-being.  
 
Subjects with diary cards that are missing data for several days (i.e., less than 1 week) and 
subjects with negative laboratory confirmation who miss their follow-up serology assessment 
should be considered to have missing data.  Subjects with missing data in community and 
nursing home trials are counted as not having symptomatic, laboratory-confirmed influenza in 
the primary analysis.  A household with no confirmed cases of influenza that has at least one 
contact case withdrawn from the trial should be defined as a household with missing data.  
Households with missing data and no identified influenza cases are counted as not having 
symptomatic, laboratory-confirmed influenza in the primary analysis.   
 
Because prophylaxis failures are defined based on flu symptoms and laboratory confirmation 
with viral assays, the source of these symptoms and the performance of these assays will have an 
effect on the observed failures and, therefore, on the trial power and analysis.  The assay 
specificity (i.e., the assays ability to classify a sample as negative when it is truly negative) is 
likely to have the most influence.  The use of a highly specific and sensitive assay or assays 
(such as RT-PCR) is of great importance in increasing trial power.  Sponsors should provide a 
detailed description of the assays methodology and supporting sensitivity and specificity data 
with isolates representing the diversity of influenza viruses. 
 
Sponsors must ensure that pertinent investigational records such as diary cards and copies of the 
original laboratory sheets are retained so that they are available at the time of any FDA 
inspection (21 CFR 312.62(c)). 
 
9.  Accelerated Approval (Subpart H) Considerations  
 
The criteria described in regulations in 21 CFR part 314, subpart H (accelerated approval based 
on a surrogate endpoint considered reasonably likely to predict clinical benefit in patients with a 
22 
 Contains Nonbinding Recommendations 
serious or life-threatening disease)22 have not been used for approval of influenza antivirals, and 
are unlikely to be appropriate in most instances, because typical influenza clinical trials involve 
direct assessment of immediate clinical outcomes for an acute uncomplicated illness. In 
addition, virologic parameters have not been shown to reliably predict clinical outcomes in 
influenza trials. If situations arise in which sponsors wish to propose development under 
accelerated approval regulations, the proposals submitted for discussion and feedback should 
address the issues related to efficacy assessment and endpoint selection outlined in other sections 
of this guidance, and should also indicate how the subpart H requirements for subsequent clinical 
endpoint confirmation of benefit would be fulfilled.  
 
10.  Risk-Benefit Considerations 
 
The balance between potential risks and benefits of influenza interventions has been discussed 
elsewhere in this guidance, and should be considered throughout the influenza drug development 
process. Risk-benefit considerations are likely to be affected by the public health need (e.g., 
severity of an influenza epidemic or pandemic, virulence of circulating influenza strains, 
epidemiology of illness and complications, and availability of vaccine), the status of antiviral 
drug and vaccine supplies, and the apparent effect of other available anti-influenza drugs.  
Emergence of drug resistance and viral strain susceptibility should also be part of risk-benefit 
assessments.  
 
C.  Other Considerations 
 
1.  Relevant Nonclinical Safety Considerations 
 
Although influenza treatment is usually short-term and prophylaxis often lasts no more than a 
few weeks, the possibility of multiple courses of treatment or prophylaxis over a series of 
influenza seasons should be taken into account in determining the nature and duration of 
nonclinical safety studies. For instance, if the indication for a drug is treatment of influenza, 
long-term carcinogenicity studies in rodents usually are not needed.  If, on the other hand, the 
drug is indicated for the prophylaxis of influenza, carcinogenicity studies in rats and mice should 
be carried out before approval because drugs used frequently in an intermittent manner in the 
treatment of chronic or recurrent conditions generally should be supported by such studies.  The 
ICH guidance for industry S1A The Need for Long-Term Rodent Carcinogenicity Studies of 
Pharmaceuticals provides detailed information concerning the conditions under which 
carcinogenicity studies should be conducted.   
 
2.  PK and PD Considerations 
 
a.  PK measurement 
 
Several administration routes have been considered for influenza drugs:  oral, parenteral, 
inhalation, and intranasal. For oral and parenteral administration, plasma drug concentrations are 
presumed to be correlated with concentrations at site of action, although prediction of clinical 
                                                 
22 Similar considerations apply  to therapeutic  proteins or monoclonal antibodies that might be proposed  for 
development under the corresponding biologics regulations in 21 CFR part 601, subpart E.  
23 
 Contains Nonbinding Recommendations 
effect cannot be assumed in this setting.  However, for inhalation and intranasal administration in 
prophylaxis or in treatment of typical influenza, drug concentrations at the epithelial layer of 
trachea, bronchi, bronchioles, and lung may better correlate with the drugs antiviral activity.  
Avian influenza or novel influenza strains may  have a tendency to replicate outside the 
respiratory system, necessitating systemic exposure of an antiviral drug.  
 
Concentrations in the nasal cavity, respiratory tract, and lung can be estimated from nasal wash, 
sputum (by sputum induction), and bronchioalveolar lavage, respectively.  Imaging also can be 
applied during influenza drug development.  Technetium-99 scintigraphy is a technology 
currently used to quantify the percentage of dose or mass of drug deposited in the lungs, 
oropharynx, and nasopharyngeal cavity after inhalation or nasal drug delivery.  The main 
purpose of a technetium-99 scintigraphy study is to select devices, formulations, and 
administration routes during drug development.  Fluorescent imaging (e.g., fluorine-19 imaging) 
may estimate drug concentrations in the respiratory tract.  All of the above methods are 
somewhat exploratory and have not been shown to be directly suitable for regulatory purposes 
such as labeling or approval decisions. However, comparing drug concentrations in a targeted 
organ to cell culture EC  values or antiviral activity data from animals with similar 
50
concentrations in a targeted organ may help select doses for clinical trials.  
 
b.  PD measurement 
 
Virologic response or clinical endpoints can be used as response metrics in the exposure-
response evaluations. Viral titer in nasal wash has been used as a measure of virologic response; 
however, viral titer reduction in nasal wash should not be used as a primary endpoint supporting 
drug approval. For prophylaxis trials, the clinical endpoint should be used (i.e., percentage of 
subjects developing symptomatic, laboratory-confirmed influenza during prophylaxis).  
Relationships between each of these assessments and the primary efficacy endpoints should be 
assessed based on all available data. 
 
Viral samples from the throat and rectum can be analyzed for sporadic human infections with 
avian influenza strains, because avian influenza viruses generally show highest affinities for -2-
3 linked sialic acid, which is the dominating receptor type in epithelial tissues of gut and lung in 
influenza-infected birds.  In addition, there have been recent human avian influenza case reports 
of gastroenteritis without respiratory symptoms.23  If additional novel strains of influenza (of 
avian or other origin) show other patterns of viral distribution, other sample types might be 
considered if appropriate. 
 
Any drug exposure-related toxicity should be explored to assess the relationship of exposure to 
the adverse event, to define the highest tolerable exposure, and to determine the probability of an 
adverse event with a given exposure. This information can also guide dose adjustments for 
special populations. 
 
                                                 
23  Beigel, JH, 2005, Avian Influenza A (H5N1)  Infections  in Humans, N  Engl  J Med, 353-1374-85.  
24 
 Contains Nonbinding Recommendations 
c.  Modeling considerations 
 
Exposure-response modeling of phase 2 and/or phase 3 data should be included in a new drug 
application (NDA) to characterize relationships between drug concentrations and efficacy and 
safety.  Data from cell cultures, animal studies, and from trials of other drugs from the same class 
should be considered when an exposure-response model is developed.  Disease progression and 
response in a placebo group should be incorporated into the modeling.  Demographic data (e.g., 
sex, race, age, body weight, and vaccination status) should be collected and incorporated into the 
exposure-response model.  To increase understanding of exposure-response relationships, we 
recommend collection of viral genotype information to assess relationships between genetic 
variants (genotypes), exposure, and response outcomes, such as drug response, efficacy, safety, 
toxicity, and overall survival. If measurable baseline factors are deemed to be clinically 
significant covariates, dose adjustment and individualization may need to be considered.  
 
3.  Labeling Considerations 
 
Patient labeling is important for influenza drugs because of the possibility of extensive use by 
persons unfamiliar with the drugs.  Whether a patient package insert or MedGuide should be 
considered for this purpose depends on the extent of safety concerns and the specific 
circumstances expected for use.  If the drug may be purchased for stockpiling, see section 
III.C.6., Stockpiled Drug Products, for labeling issues related to stockpiled drugs. 
 
4.  Animal Rule (Subpart I) and Animal Model Considerations  
 
Because of the intense interest in the use of animal models for influenza drug development, this 
section discusses several specific uses of animal data.  
 
Data from animal studies can provide supporting information for human trial design or, in some  
cases, supportive information contributing to regulatory decisions (see examples in section 
III.A.1., Nonclinical and Early Phase Clinical Development Considerations).  Together with 
ongoing clinical trial development plans, animal data also can facilitate access to investigational 
drugs under IND or emergency use authorization (EUA) mechanisms.  However, because human 
clinical trials in influenza are feasible, ethical, and the best approach for characterizing safety 
and efficacy, the animal rule (21 CFR 314, subpart I, and corresponding biologics regulations in 
21 CFR 601, subpart H) is not an appropriate mechanism for approval of influenza drugs.  
Animal models in general have not been fully characterized or shown to be reliably predictive 
for influenza. Even though the value of clinical trial data of previous strains in predicting 
outcomes for novel strains is uncertain, it is not clear that animal data with a new prevalent strain 
would be more useful than clinical data of previous strains.  In addition, a strain used in animal 
studies may differ substantially from the strain that subsequently causes widespread human 
illness or a pandemic.  Thus, treatment trials in virus-challenged animals are not a substitute for 
clinical trials.   
 
25 
 Contains Nonbinding Recommendations 
5.  Emergency Access Considerations 
 
a.  IND use 
 
To prepare for use of antiviral drugs in a potential public health emergency, we encourage 
sponsors of approved or investigational antiviral drugs to prepare protocols that might be 
adaptable in a pandemic or other emergency setting and that can be rapidly finalized and 
implemented in a form appropriate to the circumstances.  These protocols should be designed 
both to guide use of the drug and to collect data that can contribute to improvements in use, 
including support for assessment of both efficacy and safety wherever appropriate.  However, 
given the conditions under which the drug may be administered in these protocols, protocol 
design should be simple and streamlined to answer a few relatively simple questions.  Reasons 
for advance preparation of such protocols for use in an emergency situation include: 
 
 	  Advance consideration of protocols may help facilitate emergency readiness and data 
collection 
 
 	  Protocols may benefit patients in an emergency by guiding clinical decisions about the 
continuation or modification of treatment interventions 
 
 	  Protocols may support revisions of other ongoing protocols or development of future 
protocols 
 
 	  Protocols may help avoid continued diversion of resources into use of investigational 
interventions that subsequently show lack of efficacy or unacceptable toxicity  
 
 	  Protocols may enhance understanding of other potentially important interventions as the 
pandemic extends through its phases 
 
 	  Protocols may remind health care professionals of dose adjustments and basic safety 
follow-up that can contribute to patient management and draw attention to major new 
safety or resistance concerns that can improve management of subsequent patients  
 
 	  Data from a suitably designed protocol in an emergency situation may help support future 
regulatory actions 
 
When designing protocols, sponsors should consider collection of natural history information for 
illness caused by a novel strain, flexible designs to encompass widespread mild or severe 
disease, and incorporation of monitoring and stopping rules to facilitate trial modification as 
more is learned about a novel viral strain and associated disease.   
 
b.  Emergency use authorization 
 
The Project BioShield Act (Public Law 108-276) permits the FDA to authorize the use of an 
unapproved drug or the unapproved use of an approved drug in an actual or potential emergency 
during the effective period of a declaration of an emergency.  An EUA may be issued for a 
26 
 Contains Nonbinding Recommendations 
specific drug if the totality of available scientific evidence indicates that it may be effective for 
diagnosing, preventing, or treating a serious or life-threatening disease or condition.24  We 
anticipate that drugs considered for use under an EUA will have substantially more data than that 
required to support administration to subjects under an early IND protocol so that an appropriate 
risk-benefit evaluation can be made to decide whether an EUA is justified. 
 
In most instances, the route toward use of a drug under an EUA includes both nonclinical studies 
and clinical trials directed toward influenza drug development.  Information from studies in 
animal models, or human challenge trials, in combination with other human clinical trial data 
appropriate to the development stage, contribute to the evaluation of an EUA proposal.  EUA 
proposals should contain sufficient information to justify dosing regimens and potential for 
antiviral activity and clinical benefit, and to evaluate potential risks.  In EUA proposals, it is also 
important to consider dosing recommendations for populations such as children, pregnant 
women, and individuals with renal insufficiency that may be at higher risk of influenza 
complications.  If a potential EUA requestor believes consideration of EUA status is warranted, 
the potential requestor is encouraged to contact the FDA as early as possible, to provide data in 
support of such consideration, and to engage in pre-EUA interactions with the FDA.  Such 
interactions can identify additional types of information that might be important to support the 
EUA consideration. Use of a drug under an EUA is not a clinical trial and does not take the 
place of continuing clinical trials to provide information in support of eventual submission of an 
NDA. 
 
Although INDs and EUAs might be considered either for new antiviral drugs or for new uses of 
existing drugs, the amount of new information needed may differ depending on prior experience 
with the drug, as well as factors such as the intended population (e.g., treatment of seriously ill 
patients without other treatment options versus prophylaxis of low-risk persons likely to have 
good outcome without treatment).   
 
6.  Stockpiled Drug Products 
 
Approved drugs, or investigational drugs with sufficient safety and efficacy data to consider 
widespread investigational use, can be considered for stockpiling by appropriate entities.  We do 
not make decisions regarding selection or purchase of drugs for stockpiling. However, we will 
review sponsor proposals for stockpile-specific manufacturing, labeling, and packaging.  
Information collected during initial trials can be used to develop simplified instructions for 
potential use during a pandemic.  The instructions on the container label may need to be assessed 
for clarity based on the anticipated distribution modes and whether it will be possible to provide 
additional instructions (e.g., depending on the course of a specific emergency situation it may not 
be possible for a health care professional to provide appropriate counseling).  The inclusion of 
tear-off panels with lot information for record keeping purposes may be useful in some stockpile 
situations. 
 
Sponsors who wish to propose stockpile-related packaging or instructions should provide 
information about concerns from potential purchasers that affect their packaging or labeling 
                                                 
24 See the guidance Emergency Use Authorization of  Medical Products  
(http://www.fda.gov/RegulatoryInformation/Guidances/ucm125127.htm). 
27 
 Contains Nonbinding Recommendations 
proposals. Documentation should be provided to show how the submitted proposal addresses 
priorities expressed by specified potential purchasers and how the purchasers together with the 
sponsor plan to manage any pitfalls associated with the proposed packaging or instructions.  For 
additional packaging issues for stockpiled drugs, see section III.C.7., CMC Considerations, and 
the interim final rule Exceptions or Alternatives to Labeling Requirements for Products Held by 
the Strategic National Stockpile (72 FR 73589, December 28, 2007). 
 
7.  CMC Considerations 
 
We anticipate that the chemistry, manufacturing, and controls (CMC) data for influenza drugs 
will be comparable to the CMC data for other drugs with similar uses and administration.25  We  
strongly recommend a quality-by-design approach to drug development, as well as the principles 
described in ICH guidances for industry,26 although allowances can be made in situations of dire 
need (e.g., reduced or modified expectation for stability data).   
 
Special CMC considerations may arise for drugs intended for stockpiling.  For example, because 
the distribution of stockpiled drugs during some types of pandemic conditions may take place 
rapidly and under less than ideal conditions, it may be advantageous to package such drugs in 
configurations that can be readily dispensed.  This type of packaging can include drugs in unit-
of-use bottles instead of bulk packs that require a pharmacist to dispense the appropriate number 
of tablets or capsules. Similarly, stockpiled drugs that are not taken orally might be packaged in 
kit configurations that include all associated paraphernalia such as diluents, syringes, needles, 
and delivery devices to facilitate quick drug delivery in remote conditions or under emergency 
conditions. Assembly of such a kit from separately stored components may not be feasible 
during some types of pandemic situations.  Another factor that can be considered is the use of 
packaging presentations that can be readily relabeled if the expiration dating period of the 
stockpiled drug is extended (e.g., the use of bottles instead of blister packages).   
 
If specific packaging configurations are developed, they should be described clearly and a 
scientific justification should be provided for their selection.  Stability studies should adequately 
address all climate zones where the drug may potentially be stockpiled.  Temperature cycling 
studies and humidity variation studies should be carried out to support temperature excursions 
and humidity changes that are typically encountered during stockpiling.    
 
                                                 
25  General guidance pertaining to  CMC  of drug development  can be found on  the FDA Drugs  guidance Web  page at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.   
 
26 See the ICH guidances for industry Q8(R2) Pharmaceutical Development, Q10 Pharmaceutical Quality System, 
and Q9  Quality Risk Management. 
28 
 Contains Nonbinding Recommendations 
REFERENCES27  
 
Guidances relevant to general safety and efficacy determinations 
 
Draft guidance for industry Non-Inferiority Clinical Trials28  
 
Guidance for clinical trial sponsors Establishment and Operation of Clinical Trial Data 
Monitoring Committees  
 
Guidance for industry Acceptance of Foreign Clinical Studies  
 
Guidance for industry Content and Format of Investigational New Drug Applications (INDs) for 
Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived 
Products  
 
Guidance for industry Patient-Reported Outcome Measures:  Use in Medical Product 
Development to Support Labeling Claims  
 
Guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug and 
Biological Products  
 
Guidance for industry Using a Centralized IRB Review Process in Multicenter Clinical Trials  
 
ICH guidance for industry E1A The Extent of Population Exposure to Assess Clinical Safety:  
For Drugs Intended for Long-Term Treatment of Non-Life-Threatening Conditions  
 
Guidances relevant to clinical pharmacology and exposure-response assessments 
 
Guidance for industry Exposure-Response Relationships  Study Design, Data Analysis, and 
Regulatory Applications  
 
Guidance for industry Population Pharmacokinetics  
 
Guidances relevant to nondrug influenza interventions (vaccines and diagnostics)29  
 
Guidance for industry Clinical Data Needed to Support the Licensure of Pandemic Influenza Vaccines  
(http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.ht 
m)  
                                                 
27 These guidances can be found  on the FDA Drugs guidance Web page at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm unless otherwise 
noted. 
 
28  When final, this guidance will represent the FDAs current  thinking on this topic.   
 
29 In addition to these guidances, see the CDRH Laboratory Safety Tip,  Cautions in Using Rapid Tests for Detecting  
Influenza A Viruses  
(http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/TipsandArticlesonDeviceSafety/ucm109356.htm). 
29 
 Contains Nonbinding Recommendations 
 
Guidance for industry Clinical Data Needed to Support the Licensure of Seasonal Inactivated 
Influenza Vaccines  
(http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/defa 
ult.htm)  
 
Draft guidance for industry and FDA staff Establishing the Performance Characteristics of In 
Vitro Diagnostic Devices for the Detection or Detection and Differentiation of Influenza Viruses  
(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/default.htm)30  
 
Guidance for industry and FDA Staff In Vitro Diagnostic 2009 H1N1 Tests for Use in the 2009 
H1N1 Emergency  
(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/default.htm)  
 
Guidance for industry and FDA staff In Vitro Diagnostic Devices to Detect Influenza A Viruses:  
Labeling and Regulatory Path  
(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/default.htm)  
 
Guidance for industry and FDA staff  Class II Special Controls Guidance Document:  
Reagents for Detection of Specific Novel Influenza A Viruses  
(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm0 
78583.htm)  
 
Guidance relevant to virologic assessments 
 
Guidance for industry Antiviral Product Development  Conducting and Submitting Virology 
Studies to the Agency and its attachment Guidance for Submitting Influenza Resistance Data  
 
Guidances relevant to expediting review processes and access to investigational drugs in 
settings of public health need 
 
Guidance Emergency Use Authorization of Medical Products  
(http://www.fda.gov/RegulatoryInformation/Guidances/ucm125127.htm)  
 
Guidance for industry Fast Track Drug Development Programs  Designation, Development, 
and Application Review   
 
                                                 
30  When final, this guidance will represent the FDAs current  thinking on this topic. 
30