Guidance for Industry 

Clinical Data Needed to Support the 

Licensure of Pandemic Influenza 

Vaccines 

DRAFT GUIDANCE 

This guidance document is for comment purposes only. 

Submit comments on this draft guidance by the date provided in the Federal Register notice 

announcing the availability of the draft guidance. Submit written comments to the Division of 

Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, 

Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments. 

You should identify all comments with the docket number listed in the notice of availability that 

publishes in the Federal Register. 

Additional copies of this draft guidance are available from the Office of Communication, 

Training and Manufacturers Assistance (HFM-40), 1401 Rockville Pike, Suite 200N, Rockville, 

MD 20852-1448, or by calling 1-800-835-4709 or 301-827-1800, or from the Internet at 

http://www.fda.gov/cber/guidelines.htm. 

For questions on the content of this guidance, contact Antonia Geber, M.D., or Donna Chandler, 

Ph.D., at 301-827-3070. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Biologics Evaluation and Research 

March 2006 
Contains Nonbinding Recommendations 

Draft – Not for Implementation 

Table of Contents 

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

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

III. CLINICAL DATA TO SUPPORT THE LICENSURE OF PANDEMIC 

INFLUENZA VACCINES ............................................................................................... 3

A. Approval of a Pandemic Influenza Vaccine as a Supplement to a U.S. 

Licensed Trivalent Inactivated Influenza Vaccine ............................................ 4

1. Immunogenicity .......................................................................................... 4 

2. Safety .......................................................................................................... 4 

B. Approval of a Pandemic Influenza Vaccine as a Supplement to a U.S. 

Licensed Trivalent Live Attenuated Influenza Vaccine .................................... 5

1. Immunogenicity .......................................................................................... 5 

2. Safety .......................................................................................................... 5 

C. Accelerated Approval of a BLA for a Pandemic Influenza Vaccine (i.e., Not 

as a BLA Supplement to an Existing U.S. Licensed Influenza Vaccine) ......... 6

1. Effectiveness ............................................................................................... 7 

2. Safety .......................................................................................................... 9 

3. Post-marketing Confirmatory Studies......................................................... 9 

D. Additional Considerations.................................................................................. 10

1. Types of Pandemic Influenza Vaccines .................................................... 10 

2. Clinical Lot Consistency........................................................................... 10 

3. Adjuvanted Pandemic Vaccines ............................................................... 10 

4. Alternative Routes of Administration....................................................... 11 

5. Post-marketing Studies ............................................................................. 12 

IV. REFERENCES................................................................................................................ 13

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Contains Nonbinding Recommendations 

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Guidance for Industry 

Clinical Data Needed to Support the Licensure of Pandemic 

Influenza Vaccines 

current thinking on this topic. 

does not operate to bind FDA or the public. 

If you want to 

If you cannot identify the 

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

It does not create or confer any rights for or on any person and 

 You can use an alternative approach if the 

approach satisfies the requirements of the applicable statutes and regulations. 

discuss an alternative approach, contact the appropriate FDA staff.

appropriate FDA staff, call the appropriate number listed on the title page of this guidance. 

I. INTRODUCTION 

This document is intended to provide to you, sponsors of pandemic influenza vaccines, guidance 

on clinical development approaches to facilitate and expedite the licensure of influenza vaccines 

for the prevention of disease caused by pandemic influenza viruses. The approaches apply to 

“split virus” and whole virus inactivated pandemic vaccines propagated in embryonated chicken 

eggs, and are also applicable to cell-culture derived, recombinant hemagglutinin-based protein, 

and adjuvanted pandemic influenza vaccines. We, FDA, also address live attenuated influenza 

vaccines. This document does not address influenza vaccines that do not contain a 

hemagglutinin component. Current U.S. licensed influenza vaccines are trivalent vaccines 

approved for the prevention of seasonal influenza illness. Two classes of vaccines are licensed, 

“split virus” trivalent inactivated vaccines and a live attenuated trivalent vaccine. 

This document does not address the nonclinical development of investigational vaccines. 

Successful nonclinical evaluation is an important step before proceeding with clinical 

development (Ref. 1). This document also does not address the chemistry, manufacturing, 

control, or inspection of the manufacturing facility needed for licensure. These aspects of the 

license application are addressed in the guidance document entitled, “Guidance for Industry: 

Content and Format of Chemistry, Manufacturing, and Controls Information and Establishment 

Description Information for a Vaccine or Related Product” dated January 19991

 (64 Federal 

Register 518, January 5, 1999). Sponsors may contact the Center for Biologics Evaluation and 

Research (CBER) for additional information about these aspects of vaccine development. 

1

 See http://www.fda.gov/cber/gdlns/cmcvacc.pdf. 

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

responsibilities. Instead, guidances describe the FDA’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 FDA’s guidances means that something is suggested or 

recommended, but not required. 

II. BACKGROUND 

Influenza viruses are enveloped ribonucleic acid viruses belonging to the family of 

Orthomyxoviridae and are divided into three distinct types on the basis of antigenic differences 

of internal structural proteins (Ref. 2). Two influenza types, Type A and B, are responsible for 

yearly epidemic outbreaks of respiratory illness in humans and are further classified based on the 

structure of two major external glycoproteins, hemagglutinin (HA) and neuraminidase (NA). 

Type B viruses, which are largely restricted to the human host, have a single HA and NA 

subtype. In contrast, 15 HA and 9 NA Type A influenza subtypes have been identified to date. 

Type A strains infect a wide variety of avian and mammalian species. 

Type A and B influenza variant strains emerge as a result of frequent antigenic change, 

principally from mutations in the HA and NA glycoproteins. These epidemic variants may result 

from one of two mechanisms. They may emerge as a result of selective point mutations in the 

viral genome (Refs. 3 and 4). Other epidemic variants may evolve from reassortment between 

two co-circulating strains (Refs. 5 and 6). 

Since 1977, influenza A viruses (subtype H1N1), influenza A viruses (subtype H3N2), and 

influenza B viruses have been in global circulation. The current U.S. licensed trivalent vaccines 

are formulated to prevent influenza illness caused by these influenza viruses (Ref. 7). 

Pandemic influenza outbreaks occur when a new Type A hemagglutinin subtype emerges to 

which the population has not been exposed and has little if any immunity. During the twentieth 

century, three pandemic influenza outbreaks occurred. Pandemic influenza strains can evolve 

following genetic reassortment of two co-circulating viruses, one of which originates from an 

animal reservoir and one from human origin. Such a reassortment led to the emergence of the 

1957 H2N2 subtype pandemic strain and the 1968 H3N2 subtype pandemic strain. Recent 

research suggests that the 1918-1919 H1N1 subtype pandemic strain likely resulted from a series 

of genetic mutations in multiple genes in an influenza viral strain of avian origin. These 

mutations appear to have allowed the viral strain to adapt to and spread among humans (Refs. 8, 

9, and 10). The 1918-19 H1N1 pandemic strain, the most lethal of the twentieth century, 

resulted in about 50 million deaths worldwide (Ref. 11). The genetic sequencing, phylogenetic 

analysis and reconstruction of the 1918-19 H1N1 pandemic strain have provided important new 

insights into virulence factors of influenza viruses (Refs. 9 and 10). 

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In recent years, human infections with avian influenza viruses have led to increasing concern that 

one or more of these viral strains may evolve into a pandemic viral strain that is able to spread 

among humans. Several avian subtypes have been recovered from humans with influenza 

illness. Influenza H7N7, H9N2 and H5N1 subtype strains have caused disease in humans (Refs. 

12, 13, 14, and 15). Of these, the H5N1 strains have been of most concern. Strains of this 

subtype are highly virulent with a mortality rate of approximately 50 percent among confirmed 

clinical cases. The first documented human infections with H5N1 strains occurred in Hong 

Kong in 1997 in 18 individuals, 6 of whom died. While only rare documented cases of possible 

human-to-human transmission have occurred to date (Refs. 16 and 17), H5N1 strains from more 

recent human infections between 2003 and 2005 have shown that the virus has mutated and 

variants of H5N1 strains have emerged. Information on the number of confirmed clinical cases 

due to H5N1 strains can be located at the World Health Organization’s website.2

 Of additional 

concern, recent H5N1 strains are more lethal in animal models and the host range for H5N1 

strains has expanded into mammalian species previously thought to be resistant to avian strains. 

These disturbing events have highlighted the need for influenza vaccines against potential 

pandemic strains. 

III. CLINICAL DATA TO SUPPORT THE LICENSURE OF PANDEMIC 

INFLUENZA VACCINES 

Licensure of pandemic influenza vaccines may be sought either as a supplement to an existing 

Biologics License Application (BLA) or as a new BLA using the accelerated approval 

regulations (21 CFR Part 601 Subpart E). This section provides recommendations for clinical 

data that would support such approvals for pandemic influenza vaccines. CBER has also 

prepared similar draft guidance for trivalent influenza inactivated vaccines. For an opportunity 

to comment on that guidance, please refer to CBER’s draft guidance document, “Guidance for 

Industry: Clinical Data Needed to Support the Licensure of Trivalent Inactivated Influenza 

Vaccines” dated March 2006. 

Biological products are licensed under the authority of section 351 of the Public Health Service 

Act (PHS Act) (42 U.S.C. 262). Under section 351 of the PHS Act, BLAs are approved only 

upon a showing that the product is “safe, pure and potent,” and that the manufacturing facility 

meets standards designed to assure that the biological product “continues to be safe, pure, and 

potent.” In previously issued guidance entitled, “Guidance for Industry: Providing Clinical 

Evidence of Effectiveness for Human Drug and Biological Products” dated May 1998 (section 

II.A.), FDA stated, “Potency has long been interpreted to include effectiveness (21 CFR 

600.3(s)). In 1972, FDA initiated a review of the safety and effectiveness of all previously 

licensed biologics. The Agency stated then that proof of effectiveness would consist of 

controlled clinical investigations as defined in the provision for ‘adequate and well-controlled 

2

 See www.who.int/csr/disease/avian_influenza/country/en/index.html. 

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studies’ for new drugs (21 CFR 314.126), unless waived as not applicable to the biological 

product or essential to the validity of the study when an alternative method is adequate to 

substantiate effectiveness (21 CFR 601.25(d)(2)).” 

A. Approval of a Pandemic Influenza Vaccine as a Supplement to a U.S. 

Licensed Trivalent Inactivated Influenza Vaccine 

As discussed above, clinical trials would be needed to support the appropriate dose and 

regimen of the pandemic influenza vaccine. These trials should include an assessment of 

immunogenicity and safety. Data from these trials should be submitted as a clinical 

supplement to the existing BLA. Once a pandemic influenza vaccine against a new 

influenza subtype has been licensed, further clinical data with a variant of that subtype 

would likely not be needed for licensure. Information to support a change in the viral 

subtype variant included in the vaccine should be submitted as a manufacturing 

supplement to the existing BLA. 

1. Immunogenicity 

Data to support the selected dose and regimen should be based on the evaluation of 

immune responses elicited by the vaccine. The hemagglutination inhibition (HI) 

antibody assay has been used to assess vaccine activity and may be appropriate for 

the evaluation of the pandemic influenza vaccine. Appropriate endpoints may 

include: 1) the percent of subjects achieving an HI antibody titer ≥ 1:40, and 2) rates 

of seroconversion, defined as a four-fold rise in HI antibody titer post-vaccination. 

The geometric mean titer (GMT) should be included in the results. These data and 

the 95% confidence intervals (CI) of the point estimates of these evaluations should 

be provided with the BLA clinical supplement. 

Considerable variability can be introduced into the laboratory assay used to measure 

HI antibodies as a result of a number of factors including differences in viral strains, 

red blood cell types, and the presence of non-specific inhibitors in the assay medium. 

Thus, suitable controls and assay validation are important for interpreting HI antibody 

results. Other immunologic assays, such as the microneutralization assay, might also 

be used to support the approval of a pandemic influenza vaccine as a clinical 

supplement to the BLA (Ref. 18). 

2. Safety 

Local and systemic reactogenicity events should be well defined in all age groups for 

whom approval of the vaccine is sought. Appropriate grading scales to describe the 

severity of the adverse events should be included in the study protocol. Serious 

adverse events should be monitored and collected for all subjects throughout the 

duration of the studies. The protocol should include a clinic visit or telephone contact 

at least six months post-vaccination to ascertain additional serious adverse events and 

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new onset of chronic illnesses that may have occurred in the interim. Safety data 

gathered from the six month post-vaccination evaluation should be submitted when 

available. This may occur after submission or approval of the supplement. 

It is anticipated that data will be collected in adults and in the pediatric population in 

a step-wise fashion. We assume that approval for use in the adult population, 

including the geriatric population, would be sought with the initial application. The 

amount of data needed for a particular manufacturer’s vaccine to support approval for 

use in the pediatric population should depend on available clinical data for that 

trivalent influenza vaccine. The timing of the clinical development in the pediatric 

population warrants discussion with CBER. All sponsors have obligations to study 

pediatric populations as outlined in the Pediatric Research Equity Act of 2003. 

B. Approval of a Pandemic Influenza Vaccine as a Supplement to a U.S. 

Licensed Trivalent Live Attenuated Influenza Vaccine 

As for pandemic influenza vaccines discussed in section III.A. above, clinical trials to 

support the appropriate dose and regimen of a live attenuated pandemic influenza vaccine 

would be needed and should include an assessment of immunogenicity and safety. These 

data should be submitted as a clinical supplement to the existing BLA for the trivalent 

live attenuated influenza vaccine. However, because of the theoretical concern for 

reassortment between a live attenuated pandemic influenza vaccine strain with other 

circulating influenza strains, it is anticipated that a licensed live attenuated influenza 

vaccine would be labeled for use only after the onset of a pandemic influenza outbreak. 

1. Immunogenicity 

Data to support the selected dose and regimen should be based on the evaluation of 

immune responses elicited by the vaccine. The HI antibody response may be 

appropriate for the evaluation of the new pandemic influenza vaccine strain. For the 

HI antibody assay, we recommend the following endpoints: 1) the percent of subjects 

achieving an HI antibody titer ≥ 1:40, and 2) rates of seroconversion, defined as a 

four-fold rise in HI antibody titer post-vaccination. The GMT should be included in 

the results. These data and the 95% CI of the point estimates of these evaluations 

should be provided with the BLA clinical supplement. Given the route of 

administration of live attenuated influenza vaccines, other assays especially those that 

assess mucosal immunity may also be appropriate if they are validated and are shown 

to be predictive of effectiveness. 

2. Safety 

Clinical studies with live attenuated influenza pandemic vaccines performed in 

advance of a pandemic influenza outbreak present special considerations. Subjects 

should be isolated during the study period to minimize the potential for transmission 

of the influenza vaccine viral strain. The amount and duration of vaccine shedding 

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should be well characterized from all subjects. Contact precautions should be in 

place for study subjects and study personnel for the duration of the study. Study 

personnel should be monitored for possible influenza illness and transmission of the 

influenza vaccine strain. Study subjects and study personnel with symptoms 

suggestive of influenza illness should be treated with antiviral agents pending culture 

results. 

Local and systemic reactogenicity events and symptoms of influenza illness should be 

well defined in all age groups for whom approval of the vaccine is sought. 

Appropriate grading scales to describe the severity of the adverse events should be 

included in the study protocol. Serious adverse events should be monitored and 

collected for all subjects throughout the duration of the studies. The protocol should 

include a clinic visit or telephone contact at least six months post-vaccination to 

ascertain additional serious adverse events and new onset of chronic illnesses that 

may have occurred in the interim. Safety data gathered from the six month postvaccination evaluation may be submitted post-approval. 

C. Accelerated Approval of a BLA for a Pandemic Influenza Vaccine (i.e., Not 

as a BLA Supplement to an Existing U.S. Licensed Influenza Vaccine) 

Accelerated approval may be granted for certain biological products such as pandemic 

influenza vaccines that have been studied for their safety and effectiveness in treating 

serious or life-threatening illnesses and that provide meaningful therapeutic benefit over 

existing treatments. For pandemic vaccines, the accelerated approval pathway will be 

available at least until adequate supplies of such vaccines are available. (See Accelerated 

Approval of Biological Products for Serious or Life Threatening Illnesses (21 CFR 601 

Subpart E)). 

Such an approval will be based on adequate and well-controlled clinical trials 

establishing that the product has an effect on a surrogate endpoint that is reasonably 

likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to 

predict clinical benefit (21 CFR 601.41). Approval under this section will be subject to 

the requirement that the sponsor study the biological product further, to verify and 

describe its clinical benefit, where there is uncertainty as to the relation of the surrogate 

endpoint to clinical benefit (21 CFR 601.41). Post-marketing studies must also be 

adequate and well-controlled and should be conducted with due diligence (21 CFR 

601.41). The protocols for these studies should be submitted with the original BLA. 

Marketing approval for products approved under these regulations may be withdrawn, for 

example, if the clinical study fails to verify the clinical benefit or the sponsor fails to 

perform the required post-marketing study with due diligence (21 CFR 601.43(a)(2)). 

For pandemic influenza vaccines, evaluation of an immune response elicited following 

receipt of the vaccine may serve as a surrogate endpoint that is likely to predict clinical 

benefit, that is, prevention of influenza illness and its complications. Influenza virus 

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hemagglutinins, present on viral surfaces, are important for cell-receptor binding. The 

immune response to these hemagglutinins as measured by the presence of serum HI 

antibodies is an important protective component following vaccination and/or infection. 

To date, prospectively designed studies to evaluate the effectiveness of influenza 

vaccines have not identified a specific HI antibody titer associated with protection against 

culture confirmed influenza illness. Some studies of influenza infection, including 

human challenge studies following vaccination, have suggested that HI antibody titers 

ranging from 1:15 to 1:65 may be associated with protection from illness in 50% of 

subjects and protection from illness is increased with higher titers (Refs. 19 and 20). 

Evaluations of seroconversion and GMT have been used as measures of vaccine activity 

(Refs. 21 and 22). 

For the purposes of accelerated approval of inactivated pandemic influenza vaccines, the 

HI antibody response may be an acceptable surrogate marker of activity that is 

reasonably likely to predict clinical benefit. Currently immune response data following 

receipt of live attenuated vaccines are limited. Accelerated approval of new live 

attenuated vaccines will depend on the identification of an immune surrogate that is 

reasonably likely to predict clinical benefit. 

To be considered for accelerated approval, a BLA for a pandemic influenza vaccine 

should include results from one or more adequate and well-controlled studies designed to 

meet immunogenicity endpoints and a commitment to conduct confirmatory postmarketing studies. Since each vaccine candidate is unique (e.g., particular product 

characteristics, manufacturing process, etc.), we recommend that you discuss with CBER 

early in development the adequacy of the manufacturing methods and product testing and 

the extent of the clinical data needed to license your candidate vaccine. 

1. Effectiveness 

This section describes possible approaches for establishing effectiveness based on 

immune responses under an accelerated approval. 

a. A placebo-controlled immunogenicity trial in which HI antibody responses to 

the new vaccine are assessed may be supportive of accelerated approval if the 

study was adequately powered to assess the co-primary endpoints: 1) 

seroconversion rates, and 2) percent of subjects achieving an HI antibody titer ≥

1:40. 

For example, the following, which have been modified from guidelines by the 

currently-titled, “Committee for Medicinal Products for Human Use of the 

European Medicines Agency” (Ref. 21), may support an accelerated approval of 

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trivalent inactivated vaccines.3 The following may be used as a guide in 

developing endpoints that would support accelerated approval of pandemic 

influenza vaccines. 

For adults < 65 years of age and for the pediatric population: 

• The lower bound of the 95% CI for the percent of subjects achieving 

seroconversion for HI antibody should meet or exceed 40%. 

• The lower bound of the 95% CI for the percent of subjects achieving 

an HI antibody titer ≥ 1:40 should meet or exceed 70%. 

For adults ≥ 65 years of age: 

• The lower bound of the 95% CI for the percent of subjects achieving 

seroconversion for HI antibody should meet or exceed 30%. 

• The lower bound of the 95% CI for the percent of subjects achieving 

an HI antibody titer ≥ 1:40 should meet or exceed 60%. 

b. If a U.S. licensed pandemic influenza vaccine exists against a strain for which 

the sponsor is seeking licensure of a new vaccine, a non-inferiority comparison, as 

assessed by HI antibody responses, to the U.S. licensed pandemic influenza 

vaccine may support accelerated approval. The study should be adequately 

powered to assess the co-primary endpoints: 1) GMT, and 2) seroconversion 

rates. 

For the co-primary endpoints consider the following: 

• The upper bound of the two-sided 95% CI on the ratio of the GMTs 

(GMTU.S. licensed vaccine/GMTnew vaccine) should not exceed 1.5. A 

proposal for use of a different GMT ratio should be based upon the 

characteristics of the assay that will be used to assess antibody 

responses. 

• The upper bound of the two-sided 95% CI on the difference between 

the seroconversion rates (SeroconversionU.S. licensed vaccine -

Seroconversionnew vaccine) should not exceed 10%. 

3

 CBER has prepared similar draft guidance for trivalent influenza vaccines. For an opportunity to comment on that 

guidance, please refer to CBER’s draft guidance, “Guidance for Industry: Clinical Data Needed to Support the 

Licensure of Trivalent Inactivated Influenza Vaccines” dated March 2006. 

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c. Alternative study designs that assess different endpoints and/or other immune 

responses will be reviewed by CBER and may be accepted in support of an 

accelerated approval. CBER would need to determine that the study design is 

acceptable and the proposed surrogate endpoint(s) is reasonably likely to predict 

clinical benefit. 

2. Safety 

Safety data should be collected from subjects enrolled in pre-licensure clinical trials 

intended to support the accelerated approval of a pandemic vaccine. The monitoring 

of these subjects should follow the outline described in section III.A.2. above. In 

addition, safety laboratory tests, to include hematologic and clinical chemistry 

evaluations, should be obtained pre- and post-vaccination in the first clinical 

study(ies). A total safety database large enough to rule out a serious adverse event 

that occurs at a rate of 1 in 300 may be adequate. The size of the pre-licensure safety 

database warrants discussion with CBER, especially for vaccines manufactured using 

novel processes and for adjuvanted pandemic vaccines. This determination would be 

influenced by factors such as the nature of the new manufacturing process and 

available clinical data. Safety data to support use in pediatric populations would also 

be needed and should be submitted as part of the BLA or as a supplement if the 

indication is sought at a later time. 

3. Post-marketing Confirmatory Studies 

a. Confirmatory studies if a sponsor pursues U.S. licensure of an annual TIV 

vaccine 

Sponsors seeking approval of a pandemic influenza vaccine strain are encouraged 

to pursue development of a trivalent inactivated influenza vaccine using the same 

manufacturing process as used for the pandemic influenza vaccine (see footnote 

3). Approval of the trivalent inactivated vaccine, other than through accelerated 

approval, may help fulfill the post-marketing requirement to verify the clinical 

benefit of the pandemic influenza vaccine. 

b. Confirmatory studies if a sponsor does not pursue U.S. licensure of annual 

trivalent inactivated influenza vaccine 

The sponsor would need to conduct one or more post-marketing field 

effectiveness studies to verify the clinical benefit of the vaccine. The sponsor 

should discuss its plans with CBER and include its plan or approach to conduct a 

study with its BLA application. 

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D. Additional Considerations 

1. Types of Pandemic Influenza Vaccines 

The recommendations in section III.C. above, regarding clinical data to support the 

accelerated approval of a pandemic vaccine, apply to “split virus” and whole virus 

inactivated pandemic influenza vaccines propagated in embryonated chicken eggs. 

The recommendations also apply to licensure of cell culture derived, recombinant 

hemagglutinin-based and adjuvanted pandemic influenza vaccines. Detailed 

information on product characteristics and manufacturing processes are needed for all 

new vaccines, regardless of their derivation (see footnote 1). Accelerated approval 

would not apply to a live attenuated pandemic influenza vaccine until a surrogate 

endpoint that is reasonably likely to predict clinical benefit is identified. 

2. Clinical Lot Consistency 

The objective of a clinical lot consistency study is the demonstration that three 

consecutively manufactured final bulk lots of vaccine elicit equivalent immune 

responses. The HI antibody assay may be used to assess the immune responses. We 

recommend a pair-wise comparison of the 95% CI on the ratio of GMTs for the viral 

strain contained in the three vaccine lots as an appropriate primary endpoint. The 

two-sided 95% CI on the GMT ratio should not exceed 1.5. Seroconversion rates for 

the HI antibody response for the viral strain contained in the vaccine may be assessed 

as secondary endpoints. Assessment of lot consistency may be incorporated in 

studies designed to support the accelerated approval of a new influenza vaccine. 

CBER may decide, on a case by case basis, that lot consistency may be evaluated and 

incorporated in the post-marketing commitment studies. This determination would be 

influenced by factors such as the manufacturing process used for the pandemic 

influenza vaccine and available clinical experience. 

3. Adjuvanted Pandemic Vaccines 

Small studies of inactivated pandemic influenza vaccines have shown that more 

antigen per dose and more than one dose are needed to elicit immune responses 

comparable to those elicited following a single dose of an annual trivalent inactivated 

influenza vaccine (Ref. 23). Use of an adjuvant might reduce the amount of antigen 

needed to elicit immune responses to protect against influenza illness. All influenza 

vaccine products formulated with an adjuvant should be submitted as new products. 

Data supporting their approval should be submitted to a new BLA. 

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• Dose and Formulation Selection 

At an early stage of development, the sponsor should demonstrate the added 

value of the adjuvant given with the antigen. Assuming that the vaccine is a 

hemagglutinin-based product, the HI antibody assay may be appropriate to 

evaluate the immune response. 

A comparative study of adjuvanted vs. non-adjuvanted vaccines should 

demonstrate that the immune response elicited by the adjuvanted antigen is 

significantly better than that elicited by the same antigen alone. Differences 

in HI antibody titer and seroconversion should be meaningful (i.e., significant 

by assessment of p-value). For study sample size determination, the sponsor 

should pre-define what would constitute a meaningful difference. As an 

example, CBER may view a 0.3 log10 mean difference (same as a two-fold 

difference in GMT ratio) for the HI antibody titers and a 15% difference in 

seroconversion rates as meaningful differences. The sponsor should also 

justify values assumed for the standard deviation of the log10 HI antibody 

titers. The HI antibody titers will typically require log transformation (i.e., HI 

antibody titers converted to log10 HI antibody titers) in order to produce data 

that may satisfy the normality assumption of certain parametric statistical 

tests. A t-test (or Wilcoxon rank-sum test if the normality assumption does 

not hold) may be used to compare the mean log10 HI antibody titers, and the 

Fisher’s exact test may be used to compare the seroconversion rates. Both 

tests should be one-sided at the 2.5% significance level. The study should be 

adequately powered to meet both analysis endpoints. Alternative analyses, or 

ones allowing pre-specified covariate adjustment, may be acceptable and 

should be discussed in advance with CBER. 

Selection of an appropriate dose and formulation should also be guided by the 

safety profile of the formulations and regimens being studied. 

4. Alternative Routes of Administration 

Alternative routes of influenza vaccine administration (e.g., intradermal or 

transdermal vaccination, which may involve the use of novel devices) are being 

investigated with the goal of reducing the amount of antigen needed to elicit immune 

responses that are likely to protect against influenza illness. Such strategies might 

then allow the expansion of the available vaccine supply. In cases where no novel 

manufacturing concerns are raised (such as intradermal administration of a vaccine 

formulation licensed for subcutaneous administration), approval may be possible as a 

clinical supplement to a BLA based on clinical immunogenicity and limited safety 

data. In other cases or when a sponsor is uncertain about the data needed to support 

licensure of vaccines utilizing novel delivery methods, the sponsor should consult 

with CBER early in development. 

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5. Post-marketing Studies 

a. Effectiveness 

As discussed in section III.A. above, pandemic influenza vaccines may be 

approved on the basis of immunogenicity data submitted as a clinical supplement 

to an existing BLA for a trivalent influenza vaccine. Sponsors are encouraged to 

develop plans to monitor the effectiveness of their pandemic influenza vaccine in 

the event of a pandemic outbreak. As discussed in section III.C. above, for 

pandemic influenza vaccines approved under an accelerated approval, sponsors 

will need to conduct a post-marketing effectiveness study to verify clinical 

benefit, and should include their study plans with their application. 

b. Safety

Sponsors are encouraged to develop a plan to monitor the safety of their vaccine 

in the event of a pandemic influenza outbreak. Furthermore, sponsors may wish 

to enhance the safety database of their pandemic influenza vaccine by conducting 

safety studies prior to a pandemic influenza outbreak, for example among 

individuals identified by public health authorities for pre-pandemic vaccination. 

The safety monitoring for such studies should follow the outline described in 

section III.A.2. above. Whereas all subjects would be monitored for serious 

adverse events, detailed local and systemic reactogenicity events to further 

quantify common events might be collected from a representative subset. We 

recommend that vaccines manufactured with novel processes and adjuvants be 

evaluated more extensively. In addition, FDA and the Centers for Disease 

Control and Prevention plan to conduct enhanced safety surveillance during early 

use of the vaccine. 

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IV. REFERENCES 

1. World Health Organization. WHO guidelines on nonclinical evaluation of vaccines. Annex 1. 

WHO Technical Report Series. 2005;927:31-63. 

www.who.int/biologicals/publications/trs/areas/vaccines/nonclinical_evaluation/en/. 

2. Lamb RA, Krug RM. Orthomyxoviridae: The Viruses and Their Replication. In: Fields 

Virology, Editors-in-Chief: Knipe DM and Howley PM. 4th Edition. Philadelphia, PA: 

Lippincott Williams and Wilkins, Publishers; 2001;1487-1531. 

3. Palese P, Garcia-Sastre A. Influenza vaccines: present and future. The Journal of Clinical 

Investigation. 2002;110:9-13. 

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