Guidance for Industry
 
 
Clinical Data Needed to Support the 
Licensure of Pandemic Influenza 
Vaccines 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Additional copies of this 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 the Division of Vaccines and Related 
Product Applications at 301-827-3070. 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research 
MAY 2007  Contains Nonbinding Recommendations 
 
 
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 for Manufacturers of a U.S. 
Licensed Seasonal Inactivated Influenza Vaccine where the Process for 
Manufacturing the Pandemic Influenza Vaccine is the Same..........................3 
1.  Immunogenicity................................................................................................4 
2.  Safety................................................................................................................5 
3.   Pediatrics...........................................................................................................5 
4.  Postmarketing Information...............................................................................5 
B.  Approval of a Pandemic Influenza Vaccine for Manufacturers of a U.S. 
Licensed Seasonal Live Attenuated Influenza Vaccine where the Process for 
Manufacturing the Pandemic Influenza Vaccine is the Same..........................5 
1.  Immunogenicity................................................................................................6 
2.  Safety................................................................................................................6 
3.    Postmarketing Information...............................................................................7 
C.  Accelerated Approval of a Pandemic Influenza Vaccine Manufactured by a 
Process not U.S. Licensed.....................................................................................7 
1.  Effectiveness.....................................................................................................9 
2.  Safety..............................................................................................................10 
3.  Postmarketing Confirmatory Studies..............................................................11 
4.   Postmarketing Information.............................................................................11 
D.  Additional Considerations..................................................................................12 
1.  Types of Pandemic Influenza Vaccines..........................................................12 
2.  Clinical Lot Consistency.................................................................................12 
3.  Adjuvanted Pandemic Vaccines.....................................................................12 
4.  Alternative Routes of Administration.............................................................13 
5.  Investigating Schedules for Administration for Use Prior to a Pandemic......14 
6.  Pediatric Research Equity Act........................................................................14 
7.  Postmarketing Evaluations..............................................................................15 
IV.  REFERENCES................................................................................................................16 
i  Contains Nonbinding Recommendations 
 
Guidance for Industry 
 
Clinical Data Needed to Support the Licensure of Pandemic 
Influenza Vaccines 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this 
topic.  It does not create or confer any rights for or on any person and does not operate to bind 
FDA or the public.  You can use an alternative approach if the approach satisfies the 
requirements of the applicable statutes and regulations.  If you want to discuss an alternative 
approach, contact the appropriate FDA staff.  If you cannot identify the 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 
where the intended indication is for active immunization in persons at high risk of exposure to, 
or during a pandemic caused by, pandemic influenza viruses.  We, FDA, also discuss pursuing 
licensure of an influenza vaccine for indication and usage during the prepandemic stage in 
Section III.D.5.  Investigating Schedules for Administration for Use Prior to a Pandemic.  The 
approaches in this guidance apply to both nonadjuvanted and adjuvanted hemagglutinin-based 
pandemic vaccines, including split virus, subunit, and whole virus inactivated vaccines 
propagated in embryonated chicken eggs or cell-culture, and to recombinant hemagglutinin-
based protein vaccines, and DNA vaccines that express hemagglutinin.  We also address live 
attenuated influenza vaccines.  This document does not address influenza vaccines that do not 
rely on immunity to a hemagglutinin component.  
 
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. 1  Applicants may contact the Center 
for Biologics Evaluation and Research (CBER) for additional information about these aspects of 
vaccine development. 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the FDAs 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 FDAs guidances means that something is suggested or 
recommended, but not required. 
                                                 
1 See http://www.fda.gov/cber/vaccine/vacpubs.htm. 
1  Contains Nonbinding Recommendations 
 
 
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, numerous HA and 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 variant strains may arise 
through one of two mechanisms:  selective point mutations in the viral genome (Refs. 3 and 4) or 
from reassortment between two co-circulating strains (Refs. 5 and 6).   
 
Since 1977, influenza A virus subtypes H1N1 and H3N2, and influenza B viruses have been in 
global circulation in humans.  The current U.S. licensed trivalent vaccines are formulated to 
prevent influenza illness caused by these influenza viruses (Ref. 7). 
 
Pandemic influenza outbreaks have occurred when a new Type A hemagglutinin subtype 
emerges to which the population has not been exposed and has little or no 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 strain of avian origin.  These mutations 
appear to have allowed the virus to adapt to and spread among humans (Refs. 8, 9, and 10).  The 
1918-1919 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 1918-1919 H1N1 pandemic strain have provided important insights into 
virulence factors of influenza viruses (Refs. 9 and 10). 
 
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 raised particular concern.  Strains of this 
subtype are highly virulent with a mortality rate of approximately 50 percent among confirmed 
clinical cases.  The first documented human H5N1 infections occurred in Hong Kong in 1997 in 
18 individuals, 6 of whom died.  While only rare cases of possible human-to-human transmission 
have occurred to date (Refs. 16 and 17), the number of human infections continues to increase, 
and analysis of H5N1 strains isolated from more recent human infections has shown that the 
2  Contains Nonbinding Recommendations 
 
virus continues to mutate and that new variants have emerged.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 
events have highlighted the need to develop criteria to evaluate the safety and effectiveness of 
influenza vaccines directed against potential pandemic strains. 
 
 
III.  CLINICAL DATA TO SUPPORT THE LICENSURE OF PANDEMIC 
INFLUENZA VACCINES 
 
Licensure of pandemic influenza vaccines may be sought through the submission of a Biologics 
License Application (BLA) in accordance with either the provisions in 21 CFR 601.2 or the 
accelerated approval provisions in 21 CFR Part 601 Subpart E.  This Section provides 
recommendations for clinical data needed to support such approvals for pandemic influenza 
vaccines.  CBER has prepared similar guidance for seasonal influenza inactivated vaccines, 
Guidance for Industry:  Clinical Data Needed to Support the Licensure of Seasonal Influenza 
Vaccines.3
 
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, 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 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 for Manufacturers of a U.S. 
Licensed Seasonal Inactivated Influenza Vaccine where the Process for 
Manufacturing the Pandemic Influenza Vaccine is the Same 
 
If a manufacturer holds a U.S. license for an approved BLA for a seasonal inactivated 
influenza vaccine under either the provisions in 21 CFR 601.2 or the accelerated 
approval provisions with the vaccines clinical benefit having been confirmed in a 
postmarketing study, and the manufacturing process used for the production of the 
pandemic vaccine is the same as for the licensed product, clinical immunogenicity trials  
                                                 
2 For information on the number of confirmed clinical cases due to H5N1 strains, see the World Health 
Organizations website:  www.who.int/csr/disease/avian_influenza/country/en/index.html. 
3 See http://www.fda.gov/cber/vaccine/vacpubs.htm. 
3  Contains Nonbinding Recommendations 
 
would be needed to determine the appropriate dose and regimen of a pandemic influenza 
vaccine candidate.  These trials should also include an assessment of safety.  Sponsors 
can expect that we will seek their involvement on plans to collect additional effectiveness 
and safety information when the vaccine is used (see Section III.A.4., below).  
 
All submissions for the initial licensure of a pandemic influenza vaccine should be 
submitted as BLAs, which will provide for a trade name and labeling specific to the 
pandemic vaccine.  For sponsors with existing licensed seasonal inactivated influenza 
vaccines who intend to file a BLA for a pandemic influenza vaccine that utilizes the same 
manufacturing process, we would expect that the BLA would reference the original BLA, 
including the nonclinical and chemistry, manufacturing, and controls (CMC) data in their 
original 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 percentage of subjects achieving an HI antibody 
titer  1:40, and 2) rates of seroconversion, defined as the percentage of subjects 
with either a pre-vaccination HI titer < 1:10 and a post vaccination HI titer > 1:40 
or a pre-vaccination HI titer > 1:10 and a minimum four-fold rise in post-
vaccination HI antibody titer.  In a prepandemic setting it is likely that most 
subjects will not have been exposed to the pandemic influenza viral antigen(s).  
Therefore, it is possible that vaccinated subjects may reach both suggested 
endpoints.  Thus, for studies enrolling subjects who are immunologically naive to 
the pandemic antigen, one HI antibody assay endpoint, such as the percentage of 
subjects achieving an HI antibody titer > 1:40, may be considered.  Point 
estimates and the two-sided 95% confidence intervals (CI) of these evaluations 
should be provided with the BLA.  The geometric mean titers (GMT) at pre- and 
post-vaccination should also be included. 
 
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 and 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.  It is also recommended that adequate serum 
sample volumes be obtained and stored for possible later use in confirmatory or 
comparative assay studies, if needed. 
 
Other endpoints and the corresponding immunologic assays, such as the 
microneutralization assay, might also be used to support the approval of a 
pandemic influenza vaccine BLA (Ref. 18).  Sponsors are encouraged to discuss 
their proposals with CBER early in development. 
4  Contains Nonbinding Recommendations 
 
2.  Safety 
 
Local and systemic reactogenicity 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 must be monitored and collected for all subjects 
throughout the duration of the studies (21 CFR 312.23, 312.32, 312.56, 312.60 
and 312.62).  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 post-vaccination evaluation must be submitted 
to FDA (21 CFR 312.32 and 312.33).  This may occur after submission or 
approval of the BLA.  Sponsors are encouraged to initiate an early dialogue with 
CBER to reach agreement on the size of the safety database needed to support 
product licensure.  This is especially true when there is minimal postmarketing 
experience with the U.S. licensed seasonal influenza vaccine, such as immediately 
after licensure of a vaccine manufactured with a new adjuvant or using a new 
process.     
 
3.  Pediatrics 
 
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 sponsors pandemic influenza vaccine 
to support approval for use in the pediatric population will depend on available 
clinical data for that sponsors U.S. licensed seasonal influenza vaccine.  The 
timing of the clinical development in the pediatric population warrants discussion 
with CBER.  Please refer to Section III.D.  Additional Considerations, paragraph 
6, for a discussion of the Pediatric Research Equity Act (PREA). 
 
4.  Postmarketing Information 
 
All sponsors who seek licensure of a pandemic influenza vaccine should expect 
FDA to seek their involvement in working with FDA and other governmental 
agencies on plans to collect additional safety and effectiveness data, such as 
through epidemiological studies, when the vaccine is used.  Sponsors may 
indicate their intent in their BLAs postmarketing surveillance plans.  
 
B.  Approval of a Pandemic Influenza Vaccine for Manufacturers of a U.S. 
Licensed Seasonal Live Attenuated Influenza Vaccine where the Process for 
Manufacturing the Pandemic Influenza Vaccine is the Same 
 
As for inactivated pandemic influenza vaccines discussed in Section III.A. above, clinical 
trials to determine the appropriate dose and regimen of a live attenuated pandemic 
influenza vaccine would be needed and should include an assessment of immunogenicity 
5  Contains Nonbinding Recommendations 
 
and safety.  Sponsors can expect FDA to seek their involvement in plans to collect 
additional effectiveness and safety information, such as through epidemiological studies, 
should a pandemic influenza situation be declared or if use occurs in persons at high risk 
of exposure to the virus. 
 
Sponsors with licensed seasonal live attenuated influenza vaccines who intend to seek 
licensure for a pandemic influenza vaccine that utilizes the same manufacturing process 
should submit a new BLA, which will provide for a trade name and labeling specific to 
the pandemic vaccine.  We would expect that the new BLA would reference the BLA for 
the seasonal vaccine, including the nonclinical and CMC data in their original BLA.    
 
1.  Immunogenicity 
 
Data to support the selected dose and regimen should be based on the evaluation 
of immune responses elicited by the vaccine.  Live attenuated influenza vaccine 
may elicit a variety of immune responses, and the HI antibody response may be 
appropriate for the evaluation of the new pandemic influenza vaccine strain, 
helping to bridge its observed immunogenicity to seasonal vaccines for which 
clinical efficacy has been demonstrated.  However, live attenuated influenza 
vaccines may induce protection against disease through immunological 
mechanisms other than, or in addition to, HI antibodies.  Thus, sponsors may 
propose alternative endpoints for our consideration.  For the HI antibody assay, 
we recommend the following endpoints:  1) the percentage of subjects achieving 
an HI antibody titer  1:40, and 2) rates of seroconversion, defined as the 
percentage of subjects with either a pre-vaccination HI titer < 1:10 and a post 
vaccination HI titer > 1:40 or a pre-vaccination HI titer > 1:10 and a minimum 
four-fold rise in post-vaccination HI antibody titer.  In a prepandemic setting it is 
likely that most subjects will not have been exposed to the pandemic antigen(s).   
Therefore, it is possible that vaccinated subjects may reach both suggested 
endpoints.  Thus, for studies enrolling subjects who are immunologically naive to 
the pandemic influenza virus antigen(s), one HI antibody assay endpoint, such as 
the percentage of subjects achieving an HI antibody titer > 1:40, may be 
considered.  Point estimates and the two-sided 95% CIs of these evaluations 
should be provided with the BLA.  The GMTs at pre- and post-vaccination should 
also be included. 
 
2.  Safety 
 
Clinical studies with live attenuated influenza pandemic vaccines performed in 
advance of a pandemic influenza outbreak present special considerations.  
Therefore, sponsors are encouraged to initiate an early dialogue with CBER to 
agree on the size of the safety database needed to support product licensure.  
 
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 should be well characterized from all subjects.  Contact 
6  Contains Nonbinding Recommendations 
 
precautions should be in place for study subjects and study personnel for the 
duration of shedding.  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 or other microbiological 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 must be 
monitored and collected for all subjects throughout the duration of the studies (21 
CFR 312.23, 312.32, 312.56, 312.60 and 312.62).  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 post-vaccination 
evaluation must be submitted to FDA (21 CFR 312.32 and 312.33).  This may 
occur after submission or approval of the BLA. 
 
Because of theoretical concerns for reassortment between a live attenuated 
pandemic influenza vaccine strain and other circulating influenza strains, a live 
attenuated pandemic vaccine might be indicated for use only after the onset of a 
pandemic influenza outbreak.  Any plans to develop such products for potential 
use in a prepandemic setting, in particular the size of the safety database required 
to support such use, should be discussed with CBER.    
 
3.   Postmarketing Information  
 
All sponsors who seek licensure of a pandemic influenza vaccine should expect 
FDA to seek their involvement in working with FDA and other governmental 
agencies on plans to collect additional safety and effectiveness data, such as 
through epidemiological studies, when the vaccine is used.  Sponsors may 
indicate their intent in their BLAs postmarketing surveillance plans.   
 
C.  Accelerated Approval of a Pandemic Influenza Vaccine Manufactured by a 
Process not U.S. Licensed 
 
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)). 
 
7  Contains Nonbinding Recommendations 
 
Such an approval will be based on adequate and well-controlled clinical trials 
establishing that the biological 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).  Postmarketing 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 biological products approved under these regulations may be 
withdrawn, for example, if the postmarketing clinical study fails to verify clinical benefit 
or the sponsor fails to perform the required postmarketing study with due diligence (21 
CFR 601.43(a)(1) and (2)). 
 
For pandemic influenza vaccines, the 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 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 that 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 influenza vaccines are limited.  Accelerated approval of new 
live attenuated pandemic influenza 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 inactivated 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.  In addition, all sponsors who seek licensure of a pandemic 
influenza vaccine through accelerated approval should expect FDA to seek their 
involvement in working with FDA and other governmental agencies on plans to collect 
additional effectiveness and safety information, such as through epidemiological studies, 
when the vaccine is used.  Since each vaccine candidate is unique (e.g., particular product  
8  Contains Nonbinding Recommendations 
 
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.  Because our understanding of 
immune responses to various possible pandemic strains is evolving, the 
effectiveness criteria stated below are current recommended targets.  We are open 
to considering other study designs, other surrogate endpoints reasonably likely to 
predict benefit, along with other proposed performance targets for the surrogate 
endpoints described below or for other surrogate endpoints.  
 
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) percentage of subjects achieving an HI antibody 
titer  1:40.  In a prepandemic setting it is likely that most subjects will not 
have been exposed to the pandemic influenza viral antigen(s).  Therefore, it is 
possible that vaccinated subjects may reach both suggested endpoints.  Thus, 
for studies enrolling subjects who are immunologically naive to the pandemic 
influenza antigen, one HI antibody assay endpoint, such as the percentage of 
subjects achieving an HI antibody titer > 1:40, may be considered. 
 
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 seasonal inactivated vaccines.4  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 two-sided 95% CI for the percent of subjects 
achieving seroconversion for HI antibody should meet or exceed 40%. 
 
  The lower bound of the two-sided 95% CI for the percent of subjects 
achieving an HI antibody titer  1:40 should meet or exceed 70%. 
 
                                                 
4 CBER has prepared similar guidance for seasonal influenza vaccines.  See Guidance for Industry:  Clinical Data 
Needed to Support the Licensure of Seasonal Inactivated Influenza Vaccines 
(http://www.fda.gov/cber/vaccine/vacpubs.htm). 
9  Contains Nonbinding Recommendations 
 
For adults  65 years of age: 
 
  The lower bound of the two-sided 95% CI for the percent of subjects 
achieving seroconversion for HI antibody should meet or exceed 30%. 
 
  The lower bound of the two-sided 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 
(GMT   /GMT ) should not exceed 1.5.  A proposal 
U.S. licensedvaccine new vaccine
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 (Seroconversion     Seroconversion
U.S. licensed vaccine new 
) should not exceed 10 percentage points. 
vaccine
 
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 must be collected from subjects enrolled in pre-licensure clinical trials 
intended to support the accelerated approval of a pandemic vaccine (21 CFR 
312.23, 312.32, 312.56, 312.60 and 312.62).  The monitoring of these subjects 
should follow the outline described in Section III.A.2. above.  The data gathered 
six months post-vaccination evaluation should be submitted to FDA at the time of 
the BLA submission.  In addition, safety laboratory tests, including hematologic 
and clinical chemistry evaluations, should be obtained pre- and post-vaccination 
at least in the first clinical study(ies).  These may be needed in other studies, 
depending on the initial clinical studies and pre-clinical data.  A total safety 
database large enough to rule out a serious adverse event that occurs at a rate of 1 
in 300 may be sufficient when a sponsor has adequate marketing and safety 
experience with the same manufacturing process for a seasonal vaccine licensed 
10  Contains Nonbinding Recommendations 
 
outside the United States and these data are presented in the BLA and assessed as 
such.  For example, the upper limit of the two-sided 95% CI of the true serious 
adverse event rate is 0.0032 (<1 in 300) when no serious adverse event is 
observed among 1150 subjects who received vaccine in the clinical trials, using 
the Clopper-Pearson method.  However, the size of the pre-licensure safety 
database, especially for vaccines manufactured using novel processes, such as 
cell-culture, and for pandemic vaccines that contain novel adjuvants, would be 
influenced by factors such as the nature of the new manufacturing process and 
available preclinical and clinical data and should be discussed with CBER.  
Moreover, if a serious adverse event is present in a safety database of about 1,000 
subjects, and there is concern that it may be vaccine-related, then additional safety 
data may be needed.  Safety data to support use in pediatric populations would 
also be needed and should be submitted either as part of the BLA or as a clinical 
efficacy supplement at a later time, if pediatric studies are deferred under PREA.  
Please refer to Section III.D.  Additional Considerations, paragraph 6, for a 
discussion of the Pediatric Research Equity Act (PREA). 
 
3.  Postmarketing Confirmatory Studies 
     
There may be other approaches to fulfilling the postmarketing confirmatory study 
requirement to demonstrate clinical benefit under 21 CFR 601.41 than those 
recommended below.  Sponsors are encouraged to discuss their plans with CBER. 
   
a.  Confirmatory studies if a sponsor pursues U.S. licensure of a seasonal vaccine 
 
Sponsors seeking approval of a pandemic influenza vaccine strain may also 
choose to pursue development and licensure of a seasonal influenza vaccine 
using the same manufacturing process as used for the pandemic influenza 
vaccine (see footnote 4).  Approval of the seasonal vaccine, other than through 
accelerated approval, may help fulfill the postmarketing requirement to verify 
the clinical benefit of the pandemic influenza vaccine. 
 
b.   Confirmatory studies if a sponsor does not pursue U.S. licensure of a seasonal 
influenza vaccine 
 
Other approaches to demonstrating clinical benefit may be possible and 
sponsors desiring to pursue these other approaches should discuss their plans 
with CBER as soon as possible.  
  
4.  Postmarketing Information 
 
All sponsors who seek licensure of a pandemic influenza vaccine, including those 
granted accelerated approval under 21 CFR 601.41, should expect FDA to seek 
their involvement in working with FDA and other governmental agencies on  
11  Contains Nonbinding Recommendations 
 
plans to collect additional safety and effectiveness data, such as through 
epidemiological studies, when the vaccine is used.  Sponsors may indicate their 
intent in their BLAs postmarketing surveillance plans.  
 
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 both nonadjuvanted and 
adjuvanted hemagglutinin-based pandemic vaccines, including split virus, 
subunit, and whole virus inactivated vaccines propagated in embryonated chicken 
eggs or cell-culture, and to recombinant hemagglutinin-based protein vaccines, 
and DNA vaccines that express hemagglutinin.  Detailed information on product 
characteristics and manufacturing processes are needed for all new vaccines, 
regardless of their derivation (see footnote 1). 
 
2.  Clinical Lot Consistency 
 
The objective of a clinical lot consistency study is to show consistency of 
manufacturing and performance of the final product by demonstrating that three 
consecutively manufactured final formulated 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 be entirely 
within 0.67 and 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.  We may decide, on a case 
by case basis, that lot consistency may be evaluated and incorporated in the 
postmarketing commitment studies.  This determination would be influenced by 
factors such as the manufacturing process used for the pandemic influenza 
vaccine and available manufacturing and clinical experience. 
 
3.  Adjuvanted Pandemic Vaccines 
 
Small studies of inactivated nonadjuvanted pandemic influenza vaccines have 
shown that more antigen per dose and more than one dose are likely to be needed 
to elicit immune responses comparable to those elicited following a single dose of 
an annual seasonal inactivated influenza vaccine (Ref. 23).  An effective adjuvant 
might reduce the amount of antigen needed to elicit protective immune responses 
and may also have other desirable properties, such as cross protection against 
evolving strains and priming the immune system in a prepandemic setting.   
 
12  Contains Nonbinding Recommendations 
 
Data supporting the safety of the adjuvanted formulation and the added benefit 
over the unadjuvanted formulation must be submitted in the BLA (42 U.S.C. 
262(a)(2)(C)(i); 21 CFR 601.2).  At an early stage of development, clinical data 
supporting the value of adding the adjuvant should be provided, such as evidence 
of enhanced immune response, antigen-sparing effects, or other advantages, as 
should data supporting selection of the dose of the adjuvant itself.  Safety 
information in the BLA may include the safety experience obtained from 
domestic or foreign trials.  Safety experience from the same adjuvant formulated 
with other vaccine antigens may also contribute to the adjuvants safety 
evaluation.  It is expected that nonclinical and clinical information needed to 
support the safety of the adjuvant be discussed with us early in development.  
Finally, to delineate additional information about the adjuvanted vaccines safety 
profile, we may seek agreement from sponsors to conduct certain postmarketing 
studies. 
 
  Dose and Formulation Selection 
 
Assuming that the vaccine is a hemagglutinin-based product, the HI antibody 
assay may be appropriate to evaluate the immune response.   
 
For initial dose and formulation selection, a comparative clinical study of 
adjuvanted vs. non-adjuvanted vaccines that both contain the same amount of 
antigen should demonstrate that the immune response elicited by the 
adjuvanted antigen is better than that elicited by the same antigen alone.  For 
differences in HI antibody titer and seroconversion rates, the lower confidence 
limit on the appropriate point estimate excluding equality (i.e., the value 1 for 
the ratio parameter or 0 for the difference parameter) may be sufficient to 
demonstrate the added value of the adjuvant.  
 
A comparative study of an adjuvanted vaccine containing a lower amount of 
antigen than the dose-optimized non-adjuvanted vaccine formulation may be 
conducted to demonstrate non-inferior immune responses elicited by the 
adjuvanted vaccine.  Other approaches to demonstrate the value of the 
adjuvant, such as a greater ability of an adjuvanted vaccine to induce 
antibodies that cross-react with a wider variety of subtypes, strains, or clades, 
when compared to an unadjuvanted vaccine, may be possible.  Sponsors are 
encouraged to discuss their proposals 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., transdermal 
inoculation by needle or transdermal vaccination using a patch, which may 
involve the use of novel devices) are being investigated with the goals of reducing 
13  Contains Nonbinding Recommendations 
 
the amount of antigen needed to elicit immune responses that are likely to protect 
against influenza illness and of enhancing ease of vaccinations.  Such strategies 
might expand the available vaccine supply and/or increase the ease and speed of 
large scale immunization programs.  In cases where no novel manufacturing 
concerns are raised (such as intradermal administration of a pandemic vaccine 
formulation licensed for intramuscular administration) and the quantity and 
quality of the vaccine composition remains the same, approval may be possible as 
a clinical efficacy 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.  
 
5.  Investigating Schedules for Administration for Use Prior to a Pandemic 
 
Different schedules of influenza vaccine administration may also be investigated 
as a strategy for pandemic preparedness.  Studies may involve varying the number 
and strength of initial doses followed by a subsequent booster dose at different 
time periods using either homologous or heterologous antigen.  Results of these 
studies may generate information about cross-reactive antibodies induced by 
novel antigens and may help inform public health decisions about developing 
potential antigen-sparing strategies.  Sponsors are encouraged to consider 
supplementing their product development pathway to include these studies and to 
consult with CBER about study design so that these studies could support 
evaluation and approval for such indications.   
 
6.  Pediatric Research Equity Act 
 
The Pediatric Research Equity Act of 2003 (PREA) (Public Law 108-155) 
addresses drug and biological product development for pediatric uses.  All 
sponsors have obligations to study pediatric populations as outlined in PREA.  
Under PREA, all applications (or supplements) submitted under section 505 of the 
Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 355) or section 351 of 
the Public Health Service Act (PHS Act) (42 U.S.C. 262) for a new active 
ingredient, new indication, new dosage form, new dosing regimen, or new route 
of administration are to contain a pediatric assessment (pediatric clinical data) 
unless the sponsor has obtained a waiver or deferral from FDA (21 U.S.C. 355c).  
A draft guidance on the implementation of PREA was issued by FDA in 
September 2005 (Ref. 24).  As stated in that document, FDA encourages the 
submission of pediatric development plans to FDA as early as possible in the 
vaccine development process to increase understanding of vaccine 
immunogenicity, dosing, and safety information in the pediatric population.  The 
indication for a pandemic vaccine to be used during a pandemic is relevant for the 
pediatric population. 
 
14  Contains Nonbinding Recommendations 
 
7.  Postmarketing Evaluations 
 
a.   Effectiveness 
 
As discussed in Sections III.A. through C. above, pandemic influenza 
vaccines may be approved on the basis of immunogenicity data.  All sponsors 
who seek licensure of a pandemic influenza vaccine, including those granted 
accelerated approval under 21 CFR 601.41, should expect FDA to seek their 
involvement in working with FDA and other governmental agencies on plans 
to collect additional safety and effectiveness data, such as through 
epidemiological studies, when the vaccine is used.  Sponsors may indicate 
their intent in their BLA pharmacovigilance plans.  The additional data may 
allow a better understanding of the relationship between immunogenicity of 
the vaccine and clinical effectiveness.  As discussed in Section III.C. above, 
for pandemic influenza vaccines approved under an accelerated approval, 
sponsors will also need to conduct a postmarketing confirmatory study to 
verify clinical benefit, and should include their study plans with their 
application. 
 
b.   Safety 
 
As part of the BLA submission, sponsors should include a pharmacovigilance 
plan in accordance with the International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use 
(ICH E2E guidance) (Ref. 25).  Special attention should be paid to safety 
issues that might arise because of novel manufacturing processes and/or novel 
adjuvants.  FDA and the Centers for Disease Control and Prevention plan to 
conduct enhanced safety surveillance during early use of the vaccine, both 
prepandemic and during a pandemic.  FDA encourages sponsors to work in 
advance with us to develop safety surveillance strategies to best serve public 
health during a pandemic including the development and testing of 
postmarketing pandemic surveillance data gathering, communications, and 
reporting.    
 
In addition, sponsors who wish to enhance the safety database and safety-
related labeling of their pandemic use influenza vaccine may conduct safety 
studies prior to a pandemic influenza outbreak, for example among 
individuals identified by public health authorities for prepandemic 
vaccination.   
 
 
15  Contains Nonbinding Recommendations 
 
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. 
 
4.  Nakajima S, Nobusawa E, Nakajima K.  Variation in response among individuals to 
antigenic sites on the HA protein of human influenza virus may be responsible for the 
emergence of drift strains in the human population.  Virology.  2000;274:220-231. 
 
5.  Holmes EC, Ghedin E,  Miller N, Taylor J,  Bao Y, St. George K, Grenfell BT, Salzberg SL, 
Fraser CM, Lipman DJ, Taubenberger JK.  Whole-genome analysis of human influenza A 
virus reveals multiple persistent lineages and reassortment among recent H3N2 viruses.  
PLoS Biology.  2005;3:1579-1589. 
 
6.  Barr IG, Komadina N, Hurt AC, Iannello P, Tomasov C, Shaw R, Durrant C, Sjogren H, 
Hampson AW.  An influenza A(H3) reassortant was epidemic in Australia and New Zealand 
in 2003.  Journal of Medical Virology.  2005;76:391-397. 
 
7.  Centers for Disease Control and Prevention.  Prevention and control of influenza. 
Recommendations of the Advisory Committee on Immunization Practices (ACIP).  MMWR 
Morbidity and Mortality Weekly Report.  2005;54(RR-8):1-40. 
 
8.  Reid AH, Fanning TG, Janczewski TA, Lourens RM, Taubenberger JK.  Novel origin of the 
1918 pandemic influenza virus nucleoprotein gene.  Journal of Virology.  2004;78:12462-
12470. 
 
9.  Taubenberger JK, Reid AH, Lourens RM, Wang R, Jin G, Fanning TG.  Characterization of 
the 1918 influenza virus polymerase genes.  Nature.  2005;437:889-893. 
 
10. Tumpey TM, Basler CF, Aguilar PV, Zeng H, Solorzano A, Swayne DE, Cox NJ, Katz JM, 
Taubenberger JK, Palese P, Garcia-Sastre A.  Characterization of the reconstructed 1918 
Spanish influenza pandemic virus.  Science.  2005;310:77-80 
.
 
11. Johnson NPAS, Mueller J.  Updating the accounts:  Global mortality of the 1918-1920 
Spanish influenza pandemic.  Bulletin of the History of Medicine.  2002;76:105-115. 
 
16  Contains Nonbinding Recommendations 
 
12. Fouchier RAM, Schneeberger PM, Rozendaal FW, Broekman JM, Kemink SAG, Munster V, 
Kuiken T, Rimmelzwaan GF, Schutten M, van Doornum GJJ, Koch G, Bosman A, 
Koopmans M, Osterhaus ADME.  Avian influenza A virus (H7N7) associated with human 
conjunctivitis and a fatal case of acute respiratory distress syndrome.  Proceedings of the 
National Academy of Sciences of the United States of America.  2004;101:1356-1361. 
 
13. Lin YP, Shaw M, Gregory V, Cameron K, Lim W, Klimov A, Subbarao K, Guan Y, Krauss 
S, Shortridge K, Webster R, Cox N, Hay A.  Avian-to-human transmission of H9N2 subtype 
influenza A viruses:  Relationship between H9N2 and H5N1 human isolates.  Proceedings of 
the National Academy of Sciences of the United States of America.  2000;97:9654-9658. 
 
14. Claas ECJ, Osterhaus ADME, van Beek R, De Jong JC, Rimmelzwaan GF, Senne DA, 
Krauss S, Shortridge KF, Webster RG.  Human influenza A H5N1 virus related to a highly 
pathogenic avian influenza virus.  The Lancet.  1998;351:472-477. 
 
15. Subbarao K, Klimov A, Katz J, Regnery H, Lim W, Hall H, Perdue M, Swayne D, Bender C, 
Huang J, Hemphill M, Rowe T, Shaw M, Xu X, Fukuda K, Cox N.  Characterization of an 
avian influenza A (H5N1) virus isolated from a child with a fatal respiratory illness.  Science. 
1998;279:393-396. 
 
16. Ungchusak K, Auewarakul P, Dowell SF, Kitphati R, Auwanit W, Puthavathana P, 
Uiprasertkul M, Boonnak K, Pittayawonganon C, Cox NJ, Zaki SR, Thawatsupha P, 
Chittaganpitch M, Khontong R, Simmerman JM, Chunsutthiwat S.  Probable person-to-
person transmission of avian influenza A (H5N1).  The New England Journal of Medicine.  
2005;352:333-340. 
 
17. Buxton Bridges C, Katz JM, Seto WH, Chan PKS, Tsang D, Ho W, Mak KH, Lim W, Tam 
JS, Clarke M, Williams SG, Mounts AW, Bresee JS, Conn LA, Rowe T, Hu-Primmer J, 
Abernathy RA, Lu X, Cox NJ, Fukuda K.  Risk of influenza A (H5N1) infection among 
health care workers exposed to patients with influenza A (H5N1), Hong Kong.  The Journal 
of Infectious Diseases.  2000;181:344-348. 
 
18. Rowe T, Abernathy RA, Hu-Primmer J, Thompson WW, Lu X, Lim W, Fukuda K, Cox NJ, 
Katz JM.  Detection of antibody to avian influenza A (H5N1) virus in human serum by using 
a combination of serologic assays.  Journal of Clinical Microbiology.  1999;37:937-943. 
 
19. Hobson D, Curry RL, Beare AS, Ward-Gardner A.  The role of serum haemagglutination-
inhibiting antibody in protection against challenge infection with influenza A2 and B viruses.  
Journal of Hygiene (Camb).  1972;70:767-777. 
 
20. de Jong JC, Palache AM, Beyer WEP, Rimmelzwaan GF, Boon ACM, Osterhaus ADME.  
Haemagglutination-inhibiting antibody to influenza virus.  Developmental Biology (Basel).  
2003;115:6373. 
 
17  Contains Nonbinding Recommendations 
 
21. Committee for Proprietary Medicinal Products (CPMP).  Note for guidance on harmonisation 
of requirements for influenza vaccines.  CPMP/BWP/214/96.  The European Agency for the 
Evaluation of Medicinal Products (EMEA), March 1997. 
 
22. Treanor J, Keitel W, Belshe R, Campbell J, Schiff G, Zangwill K, Wolff M, Klimov A, 
Levandowski R, Lambert L.  Evaluation of a single dose of half strength inactivated 
influenza vaccine in healthy adults. Vaccine.  2002;20:1099-1105. 
 
23. Testimony of Anthony S. Fauci, M.D., Director, National Institute of Allergy and Infectious 
Diseases, National Institutes of Health, on Pandemic Influenza:  The Road to Preparedness 
before the Committee on Foreign Relations, United States Senate, November 9, 2005. 
 
24. FDA Draft Guidance for Industry:  How to Comply with the Pediatric Research Equity Act, 
September 2005 (http://www.fda.gov/cber/gdlns/pedreseq.htm).  This draft guidance, when 
finalized, will represent FDAs current thinking on that topic. 
 
25. ICH Guidance for Industry:  E2E Pharmacovigilance Planning, April 2005 
(http://www.fda.gov/cber/gdlns/ichpvp.htm). 
 
 
 
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