Guidance for Industry 

Influenza: Developing Drugs 

for Treatment and/or 

Prophylaxis 

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only. 

Comments and suggestions regarding this draft document should be submitted within 90 days of 

publication in the Federal Register of the notice announcing the availability of the draft 

guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and 

Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments 

should be identified with the docket number listed in the notice of availability that publishes in 

the Federal Register. 

For questions regarding this draft document contact Debra Birnkrant, M.D., at 301-796-1500. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

February 2009 

Clinical Antimicrobial 

I:\7927dft.doc 

02/02/09
Guidance for Industry 

Influenza: Developing Drugs 

for Treatment and/or 

Prophylaxis 

Additional copies are available from: 

Office of Communication 

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 

E-mail: druginfo@fda.hhs.gov 

Fax: 301-847-8714 

(Tel) 301-796-3400 

http://www.fda.gov/cder/guidance/index.htm 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

February 2009 

Clinical Antimicrobial 
TABLE OF CONTENTS 

I. INTRODUCTION............................................................................................................. 1

II. BACKGROUND ............................................................................................................... 2

III. DEVELOPMENT PROGRAM ....................................................................................... 3

A. General Considerations .................................................................................................................3

1. Nonclinical and Early Phase Clinical Development Considerations ..............................................3

a. Phase 2A: Challenge studies ....................................................................................................4

b. Phase 2 dose-ranging studies ....................................................................................................5

2. Drug Development Population.........................................................................................................6

3. Efficacy Considerations ...................................................................................................................6

4. Safety Considerations.......................................................................................................................8

B. Specific Efficacy Considerations for Phase 3 Trials....................................................................8

1. Study Design.....................................................................................................................................8

a. Treatment studies: Acute uncomplicated influenza .................................................................8

b. Treatment studies: Serious influenza in hospitalized patients .................................................9

c. Prophylaxis studies....................................................................................................................9

2. Study Population ............................................................................................................................10

3. Entry Criteria .................................................................................................................................11

4. Blinding ..........................................................................................................................................11

5. Special Populations........................................................................................................................11

6. Dose Selection and Route of Administration..................................................................................12

7. Efficacy Endpoints..........................................................................................................................12

a. General considerations ............................................................................................................12

b. Treatment of acute uncomplicated illness...............................................................................13

c. Seriously ill hospitalized patients............................................................................................14

d. Prophylaxis .............................................................................................................................14

e. Reduction in complications.....................................................................................................14

8. Study Procedures and Timing of Assessments................................................................................15

9. Statistical Considerations for Phase 3 Studies...............................................................................16

a. Treatment studies ....................................................................................................................17

b. Prophylaxis studies .................................................................................................................17

10. Accelerated Approval (Subpart H) Considerations...................................................................19

11. Risk-Benefit Considerations ......................................................................................................20

C. Other Considerations...................................................................................................................20

1. Relevant Nonclinical Safety Considerations ..................................................................................20

2. PK and PD Considerations ............................................................................................................20

a. PK measurement .....................................................................................................................20

b. PD measurement .....................................................................................................................21

c. Modeling considerations .........................................................................................................21

3. Labeling Considerations ................................................................................................................22

4. Animal Rule (Subpart I) Considerations ........................................................................................22

5. Emergency Use Considerations .....................................................................................................22

6. Stockpiled Drug Products ..............................................................................................................24

7. CMC Considerations......................................................................................................................24

REFERENCES............................................................................................................................ 26
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

Guidance for Industry1 1 

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Influenza: Developing Drugs for 

Treatment and/or Prophylaxis 

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8 This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current 

9 thinking on this topic. It does not create or confer any rights for or on any person and does not operate to 

10 bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of 

11 the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA 

12 staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call 

13 the appropriate number listed on the title page of this guidance. 

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I. INTRODUCTION 

The purpose of this guidance is to assist sponsors in the clinical 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 

Administration’s (FDA’s) current thinking regarding the overall development program and 

designs of clinical and nonclinical studies to support the development of influenza drug 

products.3 This guidance is intended to serve as a focus for continued discussions among the 

Division of Antiviral Products (DAVP), pharmaceutical sponsors, the academic community, and 

the public.4 As the science of influenza treatment and prophylaxis evolves, this guidance may be 

revised. 

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 

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 (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 (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. 

4

 In addition to consulting guidances, sponsors are encouraged to contact the division to discuss specific issues that 

arise during the development of influenza drug products. 

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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 development, depending on appropriate 

fulfillment of the designated criteria. 

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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.

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 This guidance focuses on specific drug development and trial design issues that are 

unique to the study of influenza. 

FDA’s guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should 

be viewed only as recommendations, unless specific regulatory or statutory requirements are 

cited. The use of the word should in Agency guidances means that something is suggested or 

recommended, but not required. 

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 studies in illness caused 

by circulating influenza virus strains. Approved antiviral drugs for influenza fall into two 

classes, adamantanes and neuraminidase inhibitors, with studies and approvals extending over 

several decades. 

Recent concerns about the possibility of pandemic spread of novel influenza strains have 

increased interest in influenza drug development;6

 however, seasonal influenza is also a major 

public health concern. The close relationship between seasonal and pandemic influenza warrant 

considering them together in 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. 

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 

5

 We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER 

guidance Web page at http://www.fda.gov/cder/guidance/index.htm. 

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 See documents and information at http://www.pandemicflu.gov. 

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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 potential pandemic strain emergence, composition of these strains cannot be 

predicted with confidence even at the subtype level. In addition, substantial additional genetic 

change is likely as a novel strain progresses from sporadic to pandemic. Once a pandemic strain 

has passed through the population, it is expected from historic example that the same subtype 

will continue to circulate for some years after the pandemic subsides. That subtype would then 

be considered as seasonal influenza, and at some point would be replaced (or dominated) by the 

next emergent pandemic variant. 

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. Thus, information on 

potential differences in drug responsiveness among strains or subtypes, including avian strains 

isolated from human infections, should be explored by generating additional data from cell 

culture and animal studies, as well as the collection of 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 drug development are of great interest. Development pathways can be 

designed to provide information supporting access to investigational drugs if public health 

emergency circumstances arise 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 could 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 studies warranted to explore risk-benefit balance (e.g., potential effects of 

immunomodulators on disease processes in patients with pre-existing immunologic 

abnormalities). 

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Candidate drugs should be assessed for activity in cell culture assays and, on the basis of those 

results, for in vivo activity in appropriate animal models of influenza infection. Sponsors should 

assess effects of candidate drugs on other pathogens that mimic or complicate influenza, 

including other respiratory viruses and bacteria associated with similar illnesses or 

complications. 

Animal studies can be used to: 

• Explore a candidate drug’s activity against various strains of influenza including novel 

strains 

• Explore the effects of inoculum size 

• Compare dosing regimens and routes of administration 

• Determine concentrations of drug at appropriate anatomic sites 

• Explore exposure-response relationships 

• Explore activity in immunocompromised hosts 

• Characterize viral resistance and transmissibility 

• Characterize treatment timing relative to onset of evident illness 

Proposals for animal studies should include supporting information on the selection and 

characterization of the 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, drug/dose and timing effects, and available 

information linking to human exposure-response and outcomes. 

Cell culture and animal model studies should not be considered a substitute for clinical trials, but 

they can make valuable contributions to clinical trial designs, including dosing considerations 

and resistance monitoring plans, and can assist in exploring the generalizability of clinical trial 

results. 

Virologic assessment and resistance monitoring are integral to antiviral drug development for 

influenza. Sponsors should address virologic plans and proposals together with their proposals 

for nonclinical and clinical studies throughout the development process beginning with pre-IND 

interactions. 

a. Phase 2A: Challenge studies 

After initial activity assessments and phase 1 human pharmacokinetic (PK) and tolerability 

studies, several sponsors have performed challenge studies. In challenge studies, healthy 

volunteers are inoculated with established challenge strains of influenza virus and administered 

an investigational antiviral drug either before (prophylaxis studies) or after (treatment studies) 

inoculation with the challenge strain. Challenge strains are attenuated viruses that produce a 

much milder set of symptoms compared to naturally occurring influenza. Pharmacodynamic 

(PD) endpoints in challenge studies include measurements such as clinical respiratory symptoms, 

nasal discharge weight, and quantitative measurements of viral shedding in nasal washes. 

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Challenge studies can provide useful exposure-response and safety information and the 

opportunity to demonstrate pharmacological antiviral activity in humans under controlled 

conditions outside the influenza season. Data from challenge studies contribute to dose selection 

for phase 2B and phase 3 studies and provide the opportunity to explore the effects of different 

times of drug initiation relative to virus exposure. However, challenge studies should not be 

considered efficacy trials for purposes of marketing approval, because challenge strains are 

attenuated viruses that produce a much milder set of symptoms compared to naturally occurring 

influenza. In addition, challenge study 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 could vary from those recognized in well-characterized 

challenge strains. 

Challenge studies are dependent on the availability of adequately safety-tested challenge strains 

and consideration of the ethics of challenge studies. Proposals for challenge studies should 

include documentation of the safety testing and biologics investigational new drug (IND) status 

(in CBER) of the influenza challenge strains. Appropriate coordination and consultation with 

CBER staff reviewing the INDs for use of any new challenge strains is important; using 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 studies on the basis of animal and human 

PK and tolerability data, cell culture EC50 values, animal model PK/PD data, and any other 

relevant information. 

b. Phase 2 dose-ranging studies 

The design of phase 2 dose-ranging studies depends on the type of population intended for phase 

3 studies, as well as the initial safety profile of the investigational drug. We strongly recommend 

that sponsors conduct phase 2 studies before designing phase 3 trials. Proceeding directly to 

phase 3 from phase 1 or phase 2A studies may fail to produce interpretable or useful phase 3 

data, especially if selection of doses and regimens are not well founded. Phase 2 dose-ranging 

studies usually are designed with statistical power to look at differences in viral shedding (e.g., 

duration, quantitative differences from baseline). Differences in clinical symptoms 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 studies are one type of adequate and wellcontrolled study that, if measuring appropriate endpoints in appropriate populations, can 

contribute to substantial evidence of effectiveness (21 CFR 314.26). In addition, exposureresponse studies and analyses within studies can provide support for approval of different doses, 

dosing regimens, or dosage forms. Depending on the study endpoints, exposure-response 

information can: 

• Help to connect in vitro antiviral activity (EC50) and exposure 

• Help to link animal and human findings 

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• In some circumstances, characterize activity against different influenza types and 

subtypes

• Allow a clear weighing of benefit and risk at different doses

At present, it is not clear what exposure parameters or PD response parameters best predict antiinfluenza efficacy outcomes. However, duration of viral shedding in nasal washes and clinical 

symptoms such as nasal congestion, feverishness, sore throat, cough, aches, fatigue, headaches, 

and chills/sweats are often measured. Typical influenza disease is restricted mostly to the 

respiratory tract and does not generally cause systemic viremia; however, there have been recent 

reports of isolation of A/H5N1 viral RNA from other organ system locations. 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. 

For detailed information on study design, see the guidances 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, sponsors also should conduct studies of persons at high risk of influenza complications 

such as the elderly, persons with underlying respiratory or cardiac disease, and 

immunocompromised persons who may not experience the same benefit or safety profile as 

otherwise healthy adults. 

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 data, they should support the data with information 

about circulating influenza strains, patterns of clinical illness, study population demographics, 

standards of medical care, and use of other medical interventions in the countries where the 

studies were conducted. The relevance of foreign data to potential drug approval in the United 

States should be evaluated according to usual regulatory policy, with consideration of study 

conduct standards, study population demographics, availability of sites for inspection, and 

applicability of disease manifestations and usual medical care to that in the United States. 

Sponsors also can consult the guidance for industry Acceptance of Foreign Clinical Studies. 

3. Efficacy Considerations 

Efficacy studies for influenza treatment focus on symptom improvement in otherwise healthy 

persons with acute uncomplicated influenza. However, large studies in otherwise healthy 

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populations may not be appropriate for some drugs with major limiting safety concerns identified 

in earlier development. 

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In general, treatment and prophylaxis indications for influenza are different indications, and each 

indication should be supported by two adequate and well-controlled studies. However, 

sometimes a single persuasive study may be sufficient for each indication, depending on other 

supportive evidence.7

 Two trials that differ in design parameters and study populations are 

usually more useful than two identically designed trials or a single large trial. For example, one 

treatment study in adults and one treatment study in children is sufficient to support a treatment 

indication in adults and children. Additional studies in special populations can be used to extend 

and further define indications. Data from studies 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. 

The DAVP has received questions regarding indications for pandemic or avian influenza (as 

contrasted with seasonal influenza) or for a specific influenza subtype. In general, molecular 

targets of antiviral drugs have not been shown to be subtype-specific; however, resistant strains 

can emerge in different subtypes and within subtypes where other strains retain activity. 

Antiviral drug efficacy against novel strains with little or no population immunity and with 

virulence factors that differ from the strains studied in clinical trials may not be predictable, but 

some effect is likely if the molecular target remains sufficiently similar.8 Information about 

strains circulating during a clinical trial is useful and should be collected and correlated with 

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 H9 has not been 

considered applicable to influenza drug development because clinical trials measure clinical 

benefit 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 most patients clear virus with or without treatment. Exploratory analyses of viral burden 

7

 The guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products

addresses desirable study attributes for the use of a single study to support approval of a drug or a new indication. 

8

 Some proposals for 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. 

9

 The analogous accelerated approval provisions for therapeutic biologics are summarized under 21 CFR part 601, 

subpart E. 

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measurements, at relevant sites, and their relationship to clinical outcomes may contribute to 

future understanding of the relationships between viral levels in clinical specimens and clinical 

outcome. 

The use of two or more antiviral drugs in combination may provide benefit greater than each 

drug alone in certain settings. Examples include treatment of serious life-threatening influenza 

illness with two drugs having synergistic or additive antiviral activity, or use of two drugs to 

delay emergence of resistance. However, combination treatment can result in increased toxicity 

and impractical dosing regimens, and/or hypothesized antiviral synergy might not occur to a 

clinically meaningful extent. Study designs should include provisions for demonstrating that 

each component of combination therapy contributes to the desired effect. 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 combination of drug and therapeutic biological product. 

Sponsors should consult 21 CFR 300.50 for specific regulatory considerations regarding fixeddose combinations. 

4. Safety Considerations 

Generation of a robust safety database from adequately blinded, well-controlled human studies in 

appropriate populations is important because of the wide variety of affected populations with a 

range of comorbidities that could interact with both disease and treatment. An application for a 

new influenza drug 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 are identified in development. Drugs that are intended to affect host cells or 

host responses, rather than directly affecting the virus, may need additional assessment for 

unintended consequences of the host alterations. 

Sponsors should provide a toxicity grading scheme for clinical trials. Commonly used schemata 

can be used (e.g., AIDS Clinical Trials Group, National Cancer Institute, or World Health 

Organization), with the understanding that toxicities with a relatively low grade assignment may 

be less acceptable in healthy populations commonly enrolled in influenza studies compared to 

populations at greater risk of serious disease outcomes, as observed in clinical trials of drugs for 

diseases such as cancer or human immunodeficiency virus. 

B. Specific Efficacy Considerations for Phase 3 Trials 

1. Study Design 

a. Treatment studies: Acute uncomplicated influenza 

Placebo-controlled studies are appropriate in settings and populations where the expected serious 

risk of nontreatment is small. Placebo-controlled rather than noninferiority designs, for studies 

evaluating treatment of uncomplicated mild to moderate influenza, 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 

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support a noninferiority margin. The variable clinical course of influenza also makes 

uncontrolled data or historical controls difficult to interpret and inadequate to support efficacy of 

investigational drugs. 

In addition to placebo-controlled studies, the following designs should be considered for 

influenza treatment studies: 1) superiority studies with approved antivirals as controls in 

otherwise healthy adults or children; 2) superiority studies with subjects receiving standard-ofcare therapy (usual care) as controls in subjects with life-threatening influenza; and 3) doseresponse (or concentration-response) studies 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 studies. 

b. Treatment studies: Serious influenza in hospitalized patients 

The availability of treatments for serious influenza in hospitalized patients is an important public 

health concern. However, there are few studies of antiviral drugs in this setting and no approved 

influenza drug has definitively demonstrated clinical efficacy in serious influenza or hospitalized 

patients. Because there are no randomized studies showing efficacy of current antiviral drugs 

against serious influenza, an active-controlled noninferiority study is not possible. Despite the 

lack of studies showing benefit of antivirals in the treatment of serious influenza, we 

acknowledge investigator concerns about randomizing hospitalized patients with serious 

influenza to placebo. Consequently, the following are reasonable study design alternatives to a 

placebo-controlled design in serious influenza: 1) a randomized dose-response study, in which a 

significant dose response is demonstrated; and 2) a superiority add-on study, 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). 

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. 

c. Prophylaxis studies 

Prophylaxis study designs include both: 1) interventions in communities after documentation of 

circulating influenza; and 2) household or institutional settings with documented exposure to a 

definite or clinically presumed case. Both sample size and risk-benefit assessments 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, placebocontrolled trials can be considered. In prophylaxis studies, the rates of symptomatic infection in 

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placebo groups vary greatly depending on the season and population, and the absolute number of 

illness outcomes in any treatment group may be small. Vaccination status and changes in 

circulating viral strains also can have effects. The small number of outcomes and resulting large 

confidence intervals in a noninferiority comparison can make establishing the effect of a new 

drug difficult. 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. 

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The most straightforward household influenza prophylaxis study design is when all symptomatic 

infected index cases receive the same care (i.e., all not treated with any active drug, all treated 

with the same study drug, or all treated with a specified alternative intervention). Households 

are then randomized to the investigational drug or control (e.g., placebo), such that all members 

of the same household receive the same assignment. This design does not provide information 

regarding whether treatment of the index case can itself decrease secondary transmission, nor 

does it provide information regarding potential interactions between the two interventions (e.g., 

reduction of prophylactic effect because of selection and shedding of resistant virus in the index 

case). A four-arm factorial-design study, in which index cases and household contacts are both 

randomized to treatment or placebo, can be used to answer questions regarding influenza 

transmission. Alternatively, sponsors can consider two or more separate studies with differing 

designs depending on the importance of each of these questions in the context of the specific 

drug. 

2. Study Population 

As mentioned, 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 studies of persons at high risk of influenza complications such as the elderly, 

persons with underlying respiratory or cardiac disease, and immunocompromised persons who 

may not experience the same benefit or safety profile. We acknowledge that it can be a 

challenge to design studies for patients at risk; however, possible study design alternatives to 

placebo-controlled designs include dose-response studies, active-controlled superiority studies, 

combination versus single therapy studies, or single arm safety studies. 

To fulfill Pediatric Research Equity Act requirements and extend treatment and/or prophylaxis 

indications to pediatric age groups, sponsors need to conduct well-controlled studies with clinical 

efficacy endpoints and complete safety evaluations.10 PK and safety studies will not be 

considered adequate to extend the indications to pediatric age groups. Antiviral drug efficacy in 

children cannot be extrapolated from studies 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. 

10 See the Pediatric Research Equity Act. 

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For treatment studies, entry criteria should include documented influenza in the community and 

occurrence of clinical influenza-like symptoms, with laboratory confirmation generally not 

available at the time treatment is initiated. 

Incorporation of a rapid test into entry criteria might lead to a more reliably influenza-positive 

population for analysis; however, all of the available tests have limitations, and the positive and 

negative predictive values of some rapid diagnostics may not be much better than clinical 

screening criteria during a seasonal epidemic. Novel influenza strains may have different test 

performance and different optimal sampling sites that may not be predictable from studies with 

previously circulating strains. 

Vaccine status can be an entry criteria or a stratification factor and is likely to affect efficacy 

outcomes. A highly vaccinated population might impair the likelihood of showing treatment 

benefit by reducing the incidence and severity of illness in the control group or may actually 

enhance detection of treatment benefit if pre-existing immunity and drug treatment are additive 

or synergistic as some studies suggest. Antiviral drugs might theoretically have deleterious 

effects on response to live-virus influenza vaccine if they are administered in the same time 

period and inhibit replication of the vaccine virus; therefore, individuals who have recently 

received a live-virus vaccine generally should be excluded from participation. Drug effects in 

response to inactivated vaccine are less likely a priori. Careful documentation of vaccine status 

and performance of appropriate interaction analyses are important parts of study design, conduct, 

and interpretation. 

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 either beneficial or adverse effects 

of drugs. 

5. Special Populations 

Populations at high risk for influenza complications include the elderly and young age groups, 

pregnant women, and people with underlying medical conditions such as pulmonary disease, 

cardiac disease, and immunosuppressive conditions. In populations at risk of serious influenza 

complications for which a placebo-controlled study may be considered undesirable, we 

recommend dose-response studies or superiority studies against an active control or standard of 

care to allow for efficacy comparisons. 

Because disease outcomes, vulnerability to adverse drug events, and overall risk-benefit 

considerations may differ in high-risk groups relative to the general population, sponsors should 

consider plans for obtaining safety and efficacy information in special populations. These plans 

should be discussed early in the development process and revised as information becomes 

available to guide such studies. Information obtained from studies in special populations also 

can provide insights into possible events in the general population in a pandemic setting. For 

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example, studies in populations with little immunity to influenza and high or prolonged viral 

replication, as reported in young children and immunocompromised patients, may provide useful 

information about likely patterns of resistance emergence and relations between dose or duration 

of treatment and outcomes in a pandemic setting. 

6. Dose Selection and Route of Administration 

Animal studies, challenge studies, and dose-ranging studies 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, and PD parameters, such as those relating to 

viral clearance, can be explored. As previously noted, we strongly recommend that sponsors 

conduct adequate phase 2 studies before designing the phase 3 trials. 

For some drugs, more than one route of administration can be considered, and different dosing, 

safety, and efficacy issues may arise with different routes of administration. For example, an 

oral form may be desirable for uncomplicated influenza while an intravenous formulation may 

be more desirable for seriously ill patients who may not be able to take oral formulations. For 

inhalation routes, determination of dosing for clinical trials based on nonclinical data can be 

challenging. In addition, if a novel strain is associated with viral replication in a broader range 

of organ systems than usual seasonal influenza, an inhalational route may be insufficient. 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 inhalation device for delivery is subject to 21 CFR part 3, 

which provides procedures for determining which FDA center has primary jurisdiction for a 

combination drug product with components potentially subject to review in different centers. 

Generally, combination drug products are regulated through the Center for Drug Evaluation and 

Research (CDER) because the drug represents the primary mechanism of action of the product. 

Drug review can involve consultation and collaboration across divisions or centers depending on 

specific attributes of each component. The sponsor of a proposed combination drug product 

should ensure that adequate information is provided 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. 

7. Efficacy Endpoints 

a. General considerations 

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 studies; however duration of defined influenza symptoms 

has been used in registrational studies of acute uncomplicated influenza. We have recently 

initiated reassessment of the approach to patient-reported components of outcome 

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measurements.11 Because of the variability of influenza illness and drug effects in past studies, 

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. 

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For both treatment and prophylaxis designs, virologic measurements are important secondary 

endpoints and can be used as components of study entry criteria or evaluability. Viral assays 

also contribute to laboratory confirmation of endpoints in prophylaxis trials. Identification of 

specific viral subtypes and strains also can be valuable for secondary analyses. Development of 

methodology for quantitative cultures at relevant sites, and for assessment of relationships 

between viral burden (including asymptomatic shedding) and secondary transmission, should be 

explored. 

Concomitant use of symptomatic relief medications may add to the difficulty of endpoint 

evaluation, but probably is not avoidable. Confounding caused by concomitant medicines may 

be lessened if protocols standardize and measure their administration. 

Assessments of influenza complications will be important if sponsors propose claims of 

reduction in complications. Objective criteria should be delineated and justified prospectively 

whenever possible, and information on the specifics of diagnosis and management should be 

collected in the protocol. 

b. Treatment of acute uncomplicated illness 

The primary endpoint in acute uncomplicated influenza treatment studies in adults should be the 

time to a defined level of symptom improvement. Components of the primary endpoint include 

fever plus a constellation of symptoms (e.g., cough, coryza, headache, body aches, sore throat). 

Secondary clinical endpoints should be time to return to normal activity and time to resolution of 

fever or other individual symptom included in the primary endpoint. 

Sponsors should propose and provide justification for a standardized and/or well-studied 

instrument for symptom measurement. We discourage adding scores for different symptom 

types into an aggregate score or area under the curve of symptoms, and consider these analyses 

exploratory because of the difficulty of equating units of severity of different symptoms. 

The primary analysis population should include all subjects with confirmed influenza (intent-totreat (ITT) infected), but additional analyses also should include all study subjects (ITT 

population). Exploratory analyses of on-treatment or per-protocol populations may be valuable 

to identify problems with dosing approaches or instructions. 

11 See the draft guidance for industry Patient-Reported Outcome Measures: Use in Medical Product 

Development to Support Labeling Claims. When final, this guidance will represent the FDA’s current 

thinking on this topic. For the most recent version of a guidance, check the CDER guidance Web page at 

http://www.fda.gov/cder/guidance/index.htm. 

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c. Seriously ill hospitalized patients 

For seriously ill influenza patients requiring hospitalization, proposed endpoints have included 

signs and symptoms, duration of hospitalization, requirements for supplemental oxygen or 

assisted ventilation, and mortality. Choice of endpoint may vary depending on the clinical 

setting and/or viral strains. A single best endpoint has not been identified in seriously ill 

hospitalized patients, and proposals should be provided for advance discussion. Duration of viral 

shedding is an important secondary endpoint that may be useful in phase 2 studies for comparing 

doses or selecting doses for phase 3 studies. 

d. Prophylaxis 

The primary endpoint for prophylaxis studies should be the occurrence of symptomatic, 

laboratory-confirmed influenza. Symptom diaries plus 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 but may reflect 

noninfluenza illnesses with symptoms similar to influenza that are not susceptible to antiinfluenza drugs and would presumably reduce effect size. 

Studies should be designed so that an appropriate range of secondary analyses can be performed 

to allow overall conclusions on the totality of the data. Analysis of all subjects with laboratory 

evidence of influenza infection, which counts both symptomatic and asymptomatic subjects as 

prophylaxis failures, can be a valuable secondary endpoint. However, the relevance of 

preventing asymptomatic infection is unclear, since the goal of influenza prophylaxis is to 

prevent symptomatic illness, and not just 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 

stopping a prophylactic drug. 

In addition to the usual primary objective of preventing symptomatic influenza illness, there is 

interest in ascertaining whether disease is milder in persons who develop influenza illness while 

receiving prophylaxis compared to persons not receiving prophylaxis. This outcome may be 

difficult to assess in most prophylaxis studies because of relatively low numbers of breakthrough 

cases with active drugs. However, if appropriate collection of symptom information is 

prospectively included during protocol planning, such severity-of-illness comparison can be a 

useful analysis to include in study design. 

e. Reduction in complications 

Findings and symptoms that are part of influenza illness should not be considered separately as 

complications if they are more properly part of a multicomponent principal endpoint. If 

complications requiring antibiotics are proposed among the study endpoints, the bacterial 

complication should fit prospectively defined criteria and appropriate expert guidelines for a 

bacterial infection requiring antibiotics. For example, many clinical diagnoses of sinusitis or 

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bronchitis may be part of the clinical spectrum of influenza itself and may not fit practice 

guidelines for antibacterial treatment. We encourage sponsors to propose prospective definitions 

of potential serious outcomes (even those outcomes expected to occur with low frequency and 

therefore not likely to have sufficient event numbers for primary analysis) to perform appropriate 

secondary analyses. 

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8. Study Procedures and Timing of Assessments 

Intensive clinical assessment is important in the period shortly after treatment initiation in 

treatment studies and presumed exposure in prophylaxis studies. The typical self-limited disease 

course may limit the ability to see treatment effects at later time points. Prophylaxis and 

treatment studies should include long enough follow-up to detect symptom recurrence after 

temporary improvement, late adverse events, or emergence of resistant virus. Protocols should 

include frequent self-assessments, with observer assessment at less frequent intervals or as 

triggered by self-assessment results. 

Available in vitro diagnostic tests for influenza use multiple methods ranging from research 

laboratory procedures to marketed test kits, and require anywhere from minutes to days for 

completion. Marketed test kits for influenza are regulated in the Center for Devices and 

Radiological Health (CDRH), and include several rapid tests designed to detect viral antigens or 

enzyme activity within 30 minutes.12 Ability to obtain specific types of diagnostic specimens, 

and to obtain a positive result in the setting of infection, may vary with factors such as severity 

of disease, age, timing, collection technique, and characteristics of novel viral strains such as 

principal anatomic distribution and sites of viral replication. Currently, FDA-cleared rapid 

diagnostic tests for influenza can be labeled as detecting influenza A, influenza A and B without 

distinguishing between 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, but clinical experience is limited to 

subtypes and strains circulating at the time trials were conducted. 

Diagnostic and monitoring assays used in a clinical trial but not FDA-cleared through CDRH are 

considered investigational. Drug sponsors should provide sufficient information on 

methodology and performance to allow evaluation of the appropriateness of the assay for its 

proposed purpose. Use of an investigational assay in a clinical trial does not constitute FDA 

approval 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. 

12 CDRH regulates in vitro diagnostic tests for influenza and has published the guidances for industry 

and FDA staff In Vitro Diagnostic Devices to Detect Influenza A Viruses: Labeling and Regulatory Path

(http://www.fda.gov/cdrh/oivd/guidance/1594.html) and Establishing the Performance Characteristics 

of In Vitro Diagnostic Devices for the Detection or Detection and Differentiation of Influenza Viruses

(http://www.fda.gov/cdrh/oivd/guidance/1638.html) on development of influenza diagnostics, 

and a Laboratory Safety Tip, Cautions in Using Rapid Tests for Detecting Influenza A Viruses

(http://www.fda.gov/cdrh/oivd/tips/rapidflu.html), that discusses cautions in the use of rapid influenza 

tests that can detect influenza virus antigens or viral enzyme activity within 30 minutes. 

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In studies designed to evaluate the efficacy of an anti-influenza drug for treatment, viral 

influenza cultures (nose and/or throat swabs or nasal wash) should be performed at baseline 

(before dosing) and at intervals during and after treatment. Duration of viral shedding is a 

valuable secondary endpoint but may be difficult to calculate if cultures are performed 

infrequently. Measurement of anti-influenza antibodies should be performed at baseline and 

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 evaluating influenza diagnosis in treatment studies and as part of the outcome 

definition of laboratory-confirmed symptomatic influenza in prophylaxis studies. Therefore, it is 

important to assess whether an antiviral drug interferes with antibody response once infection is 

established (to avoid confounding effects in treatment studies), and to evaluate the extent of 

effects on seroconversion in prophylaxis studies. 

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Subtyping and genotyping may be important for exploration of relationships to intervention 

effects, and also for identification of sources of viral transmission in studies of prophylaxis and 

transmission prevention. Baseline susceptibility and emergence of resistance to the study drug 

should be examined in clinical trials (across the range of potential study designs). If wellstandardized and generally accepted susceptibility testing methods are not available, samples 

should be saved for future testing. 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 yield different results from virus yield assays, and both may be important for 

assessment of resistance. Sponsors should consult existing guidance on virology studies and 

submission of resistance data for aspects relevant to influenza.13 

Interactions between vaccines and antiviral drugs may warrant consideration in some study 

designs. Timing of serum samples to assess seroconversion should be carefully considered to 

distinguish between antibody responses to vaccine and infection-related seroconversion as a 

diagnostic confirmation. 

Detailed viral resistance monitoring plans describing proposed analyses, sample collection times, 

assay characteristics with different influenza types and subtypes, and assay methodologies 

should be provided for review early in development, and updates 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. 

9. Statistical Considerations for Phase 3 Studies 

Sponsors should provide a protocol with a statistical analysis plan (SAP) for review and the 

protocol with the SAP should be finalized with FDA concurrence before subject enrollment. 

13 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

(http://www.fda.gov/cder/guidance/index.htm). 

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a. Treatment studies 

The primary endpoint in acute uncomplicated influenza illness treatment studies in adults should 

be the time to a defined level of symptom improvement. The primary efficacy analyses should 

focus on the population with laboratory-confirmed influenza, a baseline characteristic even if not 

defined until after baseline. Analyses of safety 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 studies is the individual study 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 worthwhile when a study 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 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 plan to deal with missing data. 

b. Prophylaxis studies 

In prophylaxis studies, the primary endpoint should be the occurrence of symptomatic, 

laboratory-confirmed influenza. 

Examples of populations that can be enrolled in prophylaxis studies, 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 study drug 

2. Index cases are treated and all contacts in a household are randomized to placebo or 

study drug 

3. Factorial studies 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 

− Index treated and contacts given placebo 

− Index untreated and contacts given prophylaxis 

− Index untreated and contacts given placebo 

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The second design is a less powerful test of prophylaxis than the first design if treating 

the index case reduces the risk to the contact cases. The third design is recommended if 

one wishes to describe both benefit of index case treatment on contact case risk and the 

benefit of contact case prophylaxis. 

In household studies, 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 there was at least one randomized contact case that 

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 become 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 the concern of drug sharing and introduce more problems with 

intrahousehold correlation. Similarly, analyses with individual contact cases as the unit 

of analysis also may introduce the same kind of problems. Stratification on size of 

household can be used but is not expected to produce any consequential increase in 

power. 

• Communities of healthy adults. For community studies with healthy adults (e.g., 

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 containing the college campus). 

• Nursing homes. For studies in nursing homes, screening, randomization, and analysis 

should be similar to that for communities of healthy adults. Nursing home studies should 

involve more careful definition and monitoring of clinical endpoints because subjects 

may lack mental acuity for self-assessment and staff will have many aspects of all 

subjects’ health to monitor. These latter concerns apply to treatment studies in nursing 

homes as well. 

In studies of prophylaxis in nursing homes and other community dwellings, the unit of 

randomization and the unit for analysis is the individual study subject. 

Statistical power in prophylaxis studies depends on the number of protocol-defined endpoint 

outcomes (symptomatic laboratory-confirmed infection) and the effect size of the intervention, 

not on the number of subjects enrolled. Therefore, the sample size of prophylaxis studies should 

be based on the number of such outcomes expected and a cautious estimate of effect size. 

Because incidence of influenza varies unpredictably from year to year, the number of subjects in 

a community prophylaxis study during one flu season may yield fewer than the number of 

influenza illnesses expected. It is advisable to monitor total number of influenza cases to see 

whether numbers are fewer than expected. Continuation of the study into a second flu season is 

appropriate if influenza attack rates are low, even if not initially specified in the protocol. There 

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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. 

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For prophylaxis studies, principal analyses and power calculations can be based on the odds ratio 

or relative risk comparing the prophylaxis failures (symptomatic, laboratory-confirmed 

influenza) for the study 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 studies 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, either in the study or if terminated from the study. 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 subject’s status 

(e.g., ascertain whether alive), a description by the subject and his or her contacts on the flu 

symptoms and adverse events, and the general well-being of the subject. 

Subjects with diary cards that are missing data for several days (i.e., less than 1 week) or 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 

studies are counted as not having symptomatic laboratory-confirmed influenza. A household 

with no confirmed cases of influenza that has at least one contact case withdraw from the study 

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 study power and analysis. The assay 

specificity (i.e., the assay’s 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 is of 

great importance in increasing study power. 

Sponsors must ensure that pertinent investigational records such as diary data and copies of 

original laboratory sheets are retained so that they are available at the time of any FDA 

inspections (21 CFR 312.62(c)). 

10. Accelerated Approval (Subpart H) Considerations 

The 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 serious or lifethreatening disease)14 have not been used for approval of influenza antivirals, and are unlikely to 

be appropriate in most instances, because usual clinical trials involve direct assessment of 

14 Similar considerations apply to therapeutic proteins or monoclonal antibodies that might be proposed for 

development under the analogous biologics regulations in 21 CFR part 601, subpart E. 

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immediate clinical outcomes for an acute uncomplicated illness. In addition, virologic 

parameters have not been shown to reliably predict clinical outcomes in influenza studies. 

11. Risk-Benefit Considerations 

The balance between potential risks and benefits of influenza interventions should be considered 

throughout the development process and are taken into account in many of the subtopics of this 

guidance. Risk-benefit considerations are likely to be affected by the status of public health need 

(e.g., severity of an influenza epidemic or pandemic, virulence of circulating influenza strains, 

epidemiology of illness and complications, availability of vaccine) and by the status of supplies 

and apparent effect of other available anti-influenza drugs. 

C. Other Considerations 

1. Relevant Nonclinical Safety Considerations 

In general, we anticipate that the nonclinical toxicology studies for influenza drugs will be 

similar to studies for other antimicrobial drugs. One question often asked about influenza drugs 

is whether animal toxicology data to support chronic administration are needed. Although 

influenza treatment is usually short-term and prophylaxis often 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 

effect cannot be assumed even 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 antiviral 

activity. Avian influenza or novel influenza strains may have a tendency to replicate outside the 

respiratory system, necessitating systemic exposure of an antiviral agent.

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 

20 
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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 the technetium-99 scintigraphy study is for selection of devices, formulations, and 

administration routes during drug development. Fluorescent imaging (e.g., flurine-19 imaging) 

may estimate 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 concentrations in a targeted organ to cell 

culture EC50 values or antiviral activity data from animals with similar concentrations in a 

targeted organ may help select doses for clinical studies. 

b. PD measurement 

Virologic response or clinical endpoints can be used as response metrics in the exposureresponse 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 principal 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 α-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. 

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. 

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 studies 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 in 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, but not limited 

to, 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.

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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 is 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) Considerations 

Because of 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 study design or, in some 

cases, can provide supportive information contributing to regulatory decisions. 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, or corresponding biologics regulations 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 reliably predictive for influenza. Even 

though the value of clinical trial data of previous strains for predicting outcomes for novel strains 

is uncertain, it is not clear that animal data with a new prevalent strain would be superior to that 

of 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. 

5. Emergency Use Considerations 

To prepare for use of antiviral drugs in a pandemic situation, sponsors of approved or 

investigational antiviral drugs are encouraged to prepare protocols that might be adaptable in a 

pandemic and that can be rapidly finalized and implemented in an emergency. Reasons for 

advance preparation of protocols for use in an emergency situation include: 

• Advance consideration of protocols may help to 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 to 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. 

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• 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. 

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• Data from a protocol in an emergency situation may help to 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 study modification as 

more is learned about a novel viral strain and associated disease. 

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 

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.15 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. 

If a drug can be considered for an EUA, advance submission and review of protocols with 

supporting information can contribute to evaluation of the authorization. Although protocol 

changes may be warranted after initial information about the emergency situation is assessed, 

preparation of basic protocols in advance of need will facilitate expert discussion and review, 

preparation for situational flexibility while preserving study integrity, and initial discussions of 

institutional review board and consent processes. 

In most instances, the route toward use of a drug under an EUA includes nonclinical and clinical 

studies directed toward influenza drug development. Information from studies in animal models, 

or human challenge studies, in combination with other human clinical trial data appropriate to 

the development stage contribute to the evaluation of an EUA proposal. 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 and to provide data in support of such 

consideration. 

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 intended population (e.g., treatment of gravely ill 

patients without other treatment options versus prophylaxis of low-risk persons likely to have 

good outcome without treatment). 

15 See the guidance Emergency Use Authorization of Medical Products

(http://www.fda.gov/oc/guidance/emergencyuse.html). 

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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 studies 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., during a pandemic it may not be possible for a health care 

professional to supply 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 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. 

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,16

although allowances could be made (e.g., reduced or modified expectation for stability data) in 

situations of dire need. Special CMC considerations may arise for drugs intended for 

stockpiling. For example, because the distribution of stockpiled drugs during a pandemic 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 a pandemic situation. 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 

16 General guidance pertaining to CMC of drug development can be found on the CDER guidance Web page at 

http://www.fda.gov/cder/guidance/index.htm. We strongly recommend a quality-by-design approach to drug 

development, as well as the principles described in the draft ICH guidances for industry Q8(R1) Pharmaceutical 

Development and Q10 Pharmaceutical Quality System and the ICH guidance for industry Q9 Quality Risk 

Management. 

24 
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25 

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studies and humidity variation studies should be carried out to support temperature excursions 

and humidity changes that are typically encountered during stockpiling. 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

REFERENCES17 1042 

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Guidances relevant to general safety and efficacy determinations 

Draft guidance for industry Patient-Reported Outcome Measures: Use in Medical Product 

Development to Support Labeling Claims

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 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)18

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/cdrh/oivd/guidance/1638.html) 

Guidance for industry Clinical Data Needed to Support the Licensure of Pandemic Influenza 

Vaccines (www.fda.gov/cber/gdlns/panfluvac.htm) 

17 These guidances can be found on the CDER guidance Web page at http://www.fda.gov/cder/guidances/index.htm 

unless otherwise noted. 

18 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/cdrh/oivd/tips/rapidflu.html). 

26 
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27 

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1096 

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Guidance for industry Clinical Data Needed to Support the Licensure of Seasonal Inactivated 

Influenza Vaccines (http://www.fda.gov/cber/gdlns/trifluvac.htm) 

Guidance for industry and FDA staff In Vitro Diagnostic Devices to Detect Influenza A Viruses: 

Labeling and Regulatory Path (http://www.fda.gov/cdrh/oivd/guidance/1594.html) 

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/cdrh/oivd/guidance/1596.html) 

Guidances relevant to virologic measurements 

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/oc/guidance/emergencyuse.html) 

Guidance for industry Fast Track Drug Development Programs — Designation, Development, 

and Application Review (http://www.fda.gov/cber/gdlns/fsttrk.htm)