Guidance for Industry
 
 
General Principles for the 
Development of Vaccines to Protect 
Against Global Infectious Diseases
 
 
 
 
 
This guidance is for immediate implementation. 
 
 
 
FDA is issuing this guidance for immediate implementation in accordance with 21 CFR 
10.115(g)(4)(i).  Submit one set of either electronic or written comments on this guidance at 
anytime.  Submit electronic comments to http://www.regulations.gov.  Submit written comments 
on this guidance at anytime to the Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.  You should identify all 
comments with Docket No. FDA-2011-D-0855.   
 
Additional copies of this guidance are available from the Office of Communication, Training and 
Manufacturers Assistance (OCOD) (HFM-40), 1401 Rockville Pike, Suite 200N, Rockville, MD 
20852-1448, or by calling 1-800-835-4709 or 301-827-1800, or e-mail ocod@fda.hhs.gov, or 
from the Internet at 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guida
nces/default.htm 
 
For questions on the content of this guidance, contact OCOD at the phone numbers or email 
address listed above.  
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research 
December 2011  Contains Nonbinding Recommendations 
 
  Table of Contents   
 
I.  INTRODUCTION.............................................................................................................1 
II.  BACKGROUND...............................................................................................................2 
III.  APPLICABLE REGULATIONS AND LEGISLATION..............................................3 
IV.  DEVELOPMENT OF VACCINES TO PROTECT AGAINST GLOBAL 
INFECTIOUS DISEASE.................................................................................................4 
A.  Foreign Clinical Studies.......................................................................................5 
B.  Human Challenge Studies....................................................................................5 
C.  Pediatric Development..........................................................................................6 
V.  FREQUENTLY ASKED QUESTIONS..........................................................................6 
VI.  REFERENCES................................................................................................................10 
 
 
 
 
 
 
 
 
i  Contains Nonbinding Recommendations 
 
Guidance for Industry 
 
General Principles for the Development of Vaccines to Protect 
  
Against Global Infectious Diseases
 
 
 
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 
 
In this guidance, we, FDA (or the Agency), provide information to assist sponsors in developing 
vaccines to protect against global infectious diseases.  The guidance will focus on development 
and licensure of vaccines targeted against infectious diseases or conditions endemic in areas 
outside the United States (U.S.).  In addition, the guidance will clarify regulations, statutes and 
guidances applicable to the development of these products.  
 
This guidance also is responsive to the congressional mandate in section 740 of the fiscal year 
2010 Appropriation Act (Agriculture, Rural Development, Food and Drug Administration, and 
Related Agencies Appropriations Act, 2010, Public Law 111-80) dated October 21, 2009.  
Among other things, this section required the Commissioner of FDA to establish two review 
groups within FDA to make recommendations on appropriate preclinical, trial design, and 
regulatory paradigms and optimal solutions to prevent, diagnose and treat rare diseases and 
neglected diseases and to develop guidance document(s) based upon these recommendations.   
 
This guidance supercedes the guidance document of the same title dated September 2008.  In this 
guidance, we are revising either the question or response or both with respect to questions 1, 3, 5, 
and 9 in section V. of this document to provide additional guidance by:  a) emphasizing that 
sponsors can apply for U.S. licensure of vaccines to protect against diseases that are not endemic 
in the U.S. and against diseases that have not been reported to occur in the U.S; b) noting that the 
accelerated approval regulations may be utilized in appropriate cases; and c) recognizing that 
when pivotal studies are conducted outside the U.S., in some instances, it may not be necessary 
to conduct studies in the U.S. and recommending that sponsors should discuss the need for such 
studies with the Center for Biologics Evaluation and Research (CBER) during clinical 
development.  All other recommendations are unchanged.  In addition, a number of 
nonsubstantive changes were made throughout the document for clarification purposes.  
 
1  Contains Nonbinding Recommendations 
 
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. 
 
 
II.  BACKGROUND 
 
The development of safe and effective vaccines to protect against global infectious diseases (e.g., 
tuberculosis, malaria, human immunodeficiency virus/acquired immunodeficiency syndrome 
(AIDS)), enteric diseases, and other neglected diseases of the developing world1 is of critical 
public health importance.  Development and availability of such vaccines, particularly for use in 
the developing countries most affected by these diseases, will benefit U.S. and global health.   
 
This guidance provides general recommendations for regulatory pathways to use in the 
development of vaccines to protect against global infectious diseases for U.S. licensure and 
clarifies applicable regulations.2  This guidance also clarifies several misconceptions 
surrounding the development of vaccines to protect against global infectious diseases in regard to 
U.S. regulatory requirements.  These clarifications are intended to ensure that potential sponsors 
and vaccine manufacturers understand that:  a) FDA can license vaccines to protect against 
infectious diseases or conditions that are not endemic or have not been reported to occur in the 
U.S.; b) the regulatory pathways to U.S. licensure for the development of vaccines to protect 
against infectious diseases that are not endemic or have not been reported to occur in the U.S. are 
                                                 
1 For purposes of this guidance, the term neglected disease of the developing world means a tropical disease, as 
defined in section 524(a)(3) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360n(a)(3))(FD&C Act).   
 
2 This guidance will not address details of clinical trial design, clinical trial conduct, endpoints, and statistical 
analysis as these are specific to the product and indication.  For general guidance on these topics, we recommend 
that you consult relevant FDA guidances (See 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm) including 
FDA guidance documents prepared under the auspices of the International Conference on Harmonisation (ICH) 
entitled, Guidance for Industry:  E8 General Considerations for Clinical Trials, Guidance for Industry:  E9 
Statistical Principles for Clinical Trials, and Guidance for Industry:  E10 Choice of Control Group and Related 
Issues in Clinical Trials (Refs. 1, 2, and 3).  Sponsors also should contact CBER for additional information about 
these aspects of vaccine development.  
 
Advances in biotechnology have resulted in novel vaccines that are presently developed against global disease (e.g., 
nucleic-acid based (DNA) vaccines, viral-vectored vaccines, recombinant fusion protein vaccines and genetically 
altered attenuated live vaccines).  These vaccines are frequently combined with novel adjuvants and administered 
using new delivery systems (e.g., needle-less injection).  Therefore, successful nonclinical safety evaluations are an 
important step in evaluating vaccines before proceeding with clinical development and are discussed in references 4 
and 5.  Furthermore, chemistry, manufacturing, control and inspection of the manufacturing facility needed for 
licensure are critical aspects of the biologics license application (BLA) and are addressed in the FDA guidance 
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 1999 (Ref. 6).  We 
encourage sponsors to discuss with us these aspects of product development during the Investigational New Drug 
Application (IND) process.   
 
2  Contains Nonbinding Recommendations 
 
the same as for vaccines to protect against diseases that are endemic in the U.S.; and c) sponsors 
may submit data from clinical trials conducted outside the U.S. to support product licensure.   
 
 
III.  APPLICABLE REGULATIONS AND LEGISLATION 
 
Current authority for the licensure and regulation of vaccines resides in section 351 of the Public 
Health Service Act (PHS Act) (42 U.S.C. 262) and numerous sections of the FD&C Act.  Section 
351 of the PHS Act provides FDA with the authority to approve marketing applications for 
biological products intended to treat, mitigate, diagnose, or prevent conditions or diseases found 
in the U.S. as well as diseases or conditions primarily endemic to other countries, or diseases or 
conditions that have not been reported to occur in the U.S.  In the Food and Drug Administration 
Amendments Act of 2007 (Public Law 110-85) dated September 27, 2007 (FDAAA), which 
amends subchapter A of chapter V of the FD&C Act (21 U.S.C. 351 et seq.) by adding section 
524, Congress recognized the importance of having products to treat and prevent tropical 
diseases that disproportionately affect poor and marginalized populations and for which there is 
no significant market in developed nations.  Under section 524, the Agency can grant priority 
review of applications under section 505(b)(1) of the FD&C Act or section 351 of the PHS Act 
for the treatment and prevention of specified tropical diseases, including tuberculosis, malaria, 
cholera, and any other infectious disease for which there is no significant market in developed 
nations and that disproportionately affects poor and marginalized populations, designated by 
regulation by the Secretary. 
 
The laws and regulations applicable for the licensure of vaccines to protect against global 
infectious diseases apply to diseases endemic in areas outside the U.S. as well as diseases 
endemic in the U.S.  Under section 351 of the PHS Act, BLAs are approved if data show 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 the FDA guidance 
entitled, Guidance for Industry: Providing Clinical Evidence of Effectiveness for Human Drug 
and Biological Products dated May 1998 (Ref. 7) (section II.A.), FDA noted that potency has 
long been interpreted to include efficacy (21 CFR 600.3(s)).  Proof of effectiveness generally 
consists of controlled clinical investigations as defined in the provision for adequate and well-
controlled studies for new drugs (See 21 CFR 314.126).  
 
The regulatory requirements contained in Title 21, Code of Federal Regulations (21 CFR) apply 
to all vaccines licensed in the U.S., regardless of their indication or intended target population.  
These regulations establish the methods and standards for manufacturing a biological product to 
assure that the product is safe and meets the quality and purity characteristics that it claims to 
possess (21 CFR Parts 600 through 680).  These regulations also cover the type of clinical 
studies that should be performed during product development (e.g., 21 CFR Parts 312, 50 and 
56).  
 
Accelerated approval may be granted for certain biological products that have been studied for 
their safety and effectiveness in treating serious or life-threatening illnesses and that provide 
meaningful therapeutic benefit to patients over existing treatments (21 CFR Part 601, Subpart E).  
 
 
3  Contains Nonbinding Recommendations 
 
 
Section 601.41 (21 CFR 601.41) sets forth the following requirements for accelerated approval: 
 
1) 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 or on 
the basis of an effect on a clinical endpoint other than survival or irreversible morbidity. 
 
2) Approval 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 or of the observed clinical benefit to ultimate outcome. 
 
3) Postmarketing studies, intended to verify the clinical benefit of the product, usually would be 
underway already, at the time of approval.  Such studies must be adequate and well-controlled 
and conducted with due diligence.  The protocols for these studies should be submitted with the 
original BLA.  Marketing approval for biological products approved under 21 CFR 601.41 or  21 
CFR 601.42 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)). 
 
In May 2002, FDA published a final rule entitled New Drug and Biological Drug Products:  
Evidence Needed to Demonstrate Effectiveness of New Drugs When Human Efficacy Studies 
Are Not Ethical or Feasible (Ref. 8).  Under this rule, FDA amended its new drug and 
biological product regulations to allow appropriate studies in animals in certain cases to provide 
substantial evidence of the effectiveness of new drug and biological products used to reduce or 
prevent the toxicity of chemical, biological, radiological, or nuclear substances (21 CFR Part 
601, Subpart H).  This rule applies when definitive human efficacy studies are not ethical or 
feasible.  In these situations, certain new drug and biological products that are intended to reduce 
or prevent serious or life-threatening conditions and for which safety has been established may 
be approved for marketing based on evidence of effectiveness derived from adequate and well-
controlled studies in animals.  In assessing the sufficiency of animal data, the Agency may take 
into account other data.  
 
 
IV.  DEVELOPMENT OF VACCINES TO PROTECT AGAINST GLOBAL 
INFECTIOUS DISEASE 
 
FDA is encouraging sponsors to develop and license vaccines to protect against global infectious 
diseases by submitting an IND (21 CFR Part 312), even if the U.S. market for that vaccine may 
be limited because the disease is not endemic or has not been reported to occur in the U.S. and 
the primary target populations for the vaccine are in developing countries.  Sponsors who are 
interested in developing these vaccines should begin interactions with the Agency early in 
product development, such as through pre-IND meetings.  Procedures and policies for the 
conduct of meetings with CBER are summarized in the FDA guidance document entitled, 
Guidance for Industry: Formal Meetings With Sponsors and Applicants for PDUFA Products 
dated February 2000 (Ref. 9). 
4  Contains Nonbinding Recommendations 
 
 
The clinical development pathway for a vaccine to protect against a global infectious disease 
depends on its indication and target population and thus, the study population, laboratory and 
clinical evaluation, trial design and endpoints chosen are specifically tailored to the product.  In 
general, the clinical immunogenicity, safety and effectiveness of a vaccine are evaluated in 
various phases of study conducted under an IND as defined in 21 CFR 312.21.  Phase 3 trials 
provide the critical documentation of the vaccines effectiveness and important additional safety 
data required for licensure.  Thus, prior to initiating Phase 3 clinical trials, we recommend that 
you discuss with us the details related to study conduct (e.g., issues related to the disease to be 
prevented or treated, study site(s), subject selection, choice of control group, trial design 
parameters such as endpoints/case definitions and diagnostic tests, dose and dosing schedule, 
study duration, concomitant vaccinations and medications, as well as safety assessments) well in 
advance of study initiation to ensure that these studies are adequately designed to meet their 
stated objectives and to support product licensure.  These trials should be conducted under the 
provisions of good clinical practice (GCP).  For FDA regulations relative to GCP and clinical 
trials, we refer you to the FDA website http://www.fda.gov/oc/gcp/regulations.html.   
 
A.  Foreign Clinical Studies 
 
For vaccines to protect against global infectious diseases, foreign efficacy trials are likely 
to be necessary if the disease of interest has a low incidence in the U.S.  There may also 
be a situation where the vaccine is developed primarily for a market outside the U.S.  
FDA has licensed vaccines based on efficacy data derived from studies solely in disease 
endemic countries (e.g., typhoid vaccine, hepatitis A vaccine, Japanese encephalitis 
vaccine, and several acellular pertussis vaccines).  
 
FDA regulations permit the acceptance of foreign clinical studies in support of a BLA 
approval, provided certain conditions are met.  Foreign studies performed under an IND 
must meet the requirements of 21 CFR Part 312.  Under 21 CFR 312.120, FDA will 
accept as support for an IND or to support an application for marketing approval, a  
well-designed and well-conducted foreign clinical study not conducted under an IND, if 
certain conditions are met, including that the study was conducted in accordance with 
GCP and including review and approval by an independent ethics committee (Ref. 10).  
For further guidance on general principles for the conduct, performance and control of 
clinical trials, refer to FDA guidance documents entitled, E6:  Good Clinical Practice: 
Consolidated Guideline dated December 1997 (Ref. 11) and E8:  Guidance on General 
Considerations for Clinical Trials dated May 1997 (Ref. 1).  In addition, it is important 
to assess the impact of ethnic factors on the vaccines safety and effectiveness.  These 
principles are discussed in the guidance document entitled, E5:  Ethnic Factors in the 
Acceptability of Foreign Clinical Data dated June 2004 (Ref. 12).  
 
B.  Human Challenge Studies 
 
In some situations, it may be possible to conduct challenge studies in human subjects 
during early development or in lieu of clinical trials in an endemic area.  Such studies 
may be conducted to demonstrate proof of concept of the vaccine antigen early in 
5  Contains Nonbinding Recommendations 
 
clinical development (e.g., Plasmodium falciparum sporozoite challenge of malaria-naive 
U.S. volunteers previously administered a candidate malaria vaccine).  Human challenge 
studies may also be conducted to demonstrate the efficacy of the vaccine.  For example, 
in 1993 and 1998, the Agency convened the Vaccines and Related Biologics Products 
Advisory Committee meetings to consider whether data from human challenge studies in 
U.S. subjects could be sufficient to demonstrate efficacy of a cholera vaccine in travelers 
to endemic areas, who are at high risk for contracting the disease.  In 1998, the committee 
agreed that human challenge studies could suffice to demonstrate efficacy of a cholera 
vaccine provided that studies were adequate and well-controlled and conducted under the 
provisions of GCP (Ref. 13).  Of note, use of challenge studies to demonstrate efficacy 
does not preclude the requirement for adequate safety data.  As human challenge studies 
may present unique considerations, we recommend that the sponsor discuss its 
development plan with CBER prior to initiation of such studies for either proof of 
concept or vaccine efficacy.   
 
C.  Pediatric Development 
 
Vaccine development generally takes place in a stepwise fashion from adults to children.  
However, for many global diseases (e.g., malaria), the pediatric population may face 
greater mortality or morbidity than the adult population because adults may already be 
immune. Therefore, it may be appropriate or necessary to start development in infants or 
children.  For pediatric studies in the U.S., institutional review boards must ensure 
research is compliant with 21 CFR Part 50, Subpart D.  The Pediatric Research Equity 
Act of 2003 (PREA), (Public Law 108-155) as reauthorized in Title IV of FDAAA, 
addresses product development for pediatric uses.  PREA requires pediatric assessments 
to be included in all applications submitted under section 505 of the FD&C Act or under 
section 351 of the PHS Act, unless the sponsor has obtained a waiver or deferral from 
FDA.  If the course of the disease and the effects of the drug are sufficiently similar in 
adults and pediatric patients, FDA may conclude that pediatric effectiveness can be 
extrapolated from adequate and well-controlled studies in adults, usually supplemented 
with other information obtained in pediatric subjects, such as immune response studies 
(section 505B(a)(2)(B) of the FD&C Act).  Sponsors must also submit adequate safety 
information to support use in the pediatric population (section 505B(a)(2)(A)(ii) of the 
FD&C Act).   
 
V.  FREQUENTLY ASKED QUESTIONS 
 
1.  What is the regulatory path forward to U.S. licensure of a vaccine to protect 
against an infectious disease that is not endemic or has not been reported to occur  
in the United States?   
 
The regulatory path for a vaccine to protect against an infectious disease that is not 
endemic or has not been reported to occur in the U.S. is the same as for a vaccine to 
protect against a disease that exists in the U.S. population.  In addition to traditional 
approval, two other pathways for approval may be utilized.  First, accelerated approval 
may be granted using a surrogate endpoint or a clinical endpoint other than survival or 
6  Contains Nonbinding Recommendations 
 
irreversible morbidity for a biological product used to treat a serious or life-threatening 
illness that provides meaningful therapeutic benefit to patients over existing treatments 
(21 CFR Part 601, Subpart E).  Approval may be subject to conducting post-marketing 
studies to verify the biological products clinical benefit, when required to be conducted.  
Second, approval may be granted based on evidence of effectiveness from studies in 
animals when human efficacy studies are not ethical or feasible (21 CFR Part 601, 
Subpart H).  In such cases, after approval, a sponsor must conduct post-marketing 
studies, such as field studies, to verify and describe the biological products clinical 
benefit and to assess its safety when used as indicated in circumstances where such 
studies are feasible and ethical; such post-marketing studies would not be feasible until 
an exigency arises (21 CFR 601.91(b)(1)).  
 
2.  How does a sponsor start interactions with CBER to develop a vaccine to 
protect against a global infectious disease? 
 
CBER encourages all sponsors that are interested in developing vaccines to begin 
interactions with us early in development, such as through pre-IND meetings (Ref. 9).  
Please call the Division of Vaccines and Related Products Applications at 301-796-2640. 
 
3.  Has CBER licensed vaccines to protect against global infectious diseases that 
are not endemic or have not been reported in the United States? 
 
Yes.  CBER has licensed vaccines for diseases that are not endemic or have not been 
reported to occur in the U.S.  These vaccines, including vaccines against typhoid, 
Japanese encephalitis, and H5N1 influenza virus, include indications for individuals 
living in or traveling to endemic areas.  
 
4.  Are the licensure requirements for a vaccine intended to be used primarily in 
other countries the same as the requirements to license a vaccine for use in the 
United States? 
 
Yes.  The requirements for CBER to license a vaccine include a demonstration that: a) 
the vaccine is safe, pure, and potent (safe and effective); and b) the facility in which the 
vaccine is manufactured complies with current good manufacturing practice (21 CFR 
601.2(d)). The level of evidence necessary to demonstrate the safety and effectiveness of 
the vaccine is the same whether or not the disease, for which the vaccine is indicated, is 
endemic to the U.S.   
 
5.  Can CBER use the accelerated approval regulations to approve vaccines 
intended to protect against global infectious diseases that are not endemic or have 
not been reported to occur in the United States?  
 
Yes.  If a surrogate endpoint is reasonably likely to predict clinical benefit, CBER can 
accept that endpoint for use in clinical trials for licensure if the product is for a serious or 
life-threatening illness and provides meaningful therapeutic benefit to patients over 
existing treatments.  CBER may approve a BLA under the accelerated approval 
7  Contains Nonbinding Recommendations 
 
regulations (21 CFR Part 601, Subpart E) with the requirement that post-marketing 
studies be performed to verify the clinical benefit of the product.   
 
6.  What does U.S. licensure signify? 
 
A U.S. license signifies to the global medical and regulatory community that the FDA has 
made the determination that the vaccine is safe and effective.  This finding by the FDA 
may assist other National Regulatory Authorities in their evaluation of the vaccine. 
 
7.  How does the submission of an IND assist sponsors in the development of 
vaccines to protect against global infectious diseases? 
 
FDA encourages submission of an IND so that it can provide input on manufacturing, 
quality testing, assay validation, non-clinical and clinical trial design issues, statistical 
analysis plans, endpoints, and other important aspects of vaccine development.  The IND 
process will allow sponsors to obtain important scientific and regulatory advice on 
products that are critical to the advancement of world health. 
 
8.  Is there a user fee for IND submissions? 
 
No.  There is no user fee for pre-IND and IND submissions or activities related to the 
IND, such as meetings and feedback from CBER to the sponsor. 
 
9.  Does CBER require that studies to support vaccine licensure be conducted in 
the United States population? 
 
There is no such requirement.  CBER evaluates trials conducted outside the U.S. to 
determine if the vaccine is safe and effective for use as proposed in labeling.  As part of 
this evaluation, CBER considers factors such as disease epidemiology, the study 
population, and the environmental and medical care conditions.  If studies to support 
vaccine licensure are conducted outside the U.S., CBER may request a smaller U.S. study 
that bridges immunogenicity and/or safety to the U.S. population.  The need to conduct 
such a study will depend on a number of factors and we encourage sponsors to discuss 
with CBER early in clinical development whether there is a need to conduct a study to 
bridge immunogenicity and/or safety to the U.S. population.   
 
10.  Does CBER require all foreign studies to be conducted under an IND to 
support approval of a BLA? 
 
Under 21 CFR 312.120, FDA will accept as support for an IND or to support an 
application for marketing approval a well-designed and well-conducted foreign clinical 
study not conducted under an IND, if certain conditions are met, including that the study 
was conducted in accordance with GCP and including review and approval by an 
independent ethics committee. 
 
 
8  Contains Nonbinding Recommendations 
 
 
11.  Is a sponsor who submits a BLA required to pay an application user fee even 
if the sponsor does not intend to market the product in the United States? 
 
Yes.  The sponsor is required to pay a user fee regardless of whether the sponsor intends 
to market the licensed product in the U.S.  However, sponsors may have the application 
user fee waived if they meet certain criteria, such as being a small business entity or 
having an orphan designation for their product.  For more information on user fees and 
waivers, see: http://www.fda.gov/ForIndustry/UserFees/default.htm 
 
12.   Are vaccines to protect against global infectious diseases that are not 
endemic or that have not been reported to occur in the United States eligible  for 
orphan designation? 
 
Yes.  A sponsor may apply for designation of its vaccine as an orphan drug if the 
vaccine is intended for use against a rare disease or condition.  Orphan drug designation 
is based on the disease prevalence in the U.S. and qualifies a sponsor to receive certain 
benefits from the government in exchange for developing the vaccine for a rare disease or 
condition.  For example, a BLA for a vaccine that has been granted orphan designation is 
not subject to an FDA user fee unless the vaccine application includes an indication other 
than for a rare disease or condition.  Orphan designation also qualifies the sponsor or 
applicant for a tax credit and marketing incentives under the Orphan Drug Act (Public 
Law 97-414) dated January 4, 1983.  In addition, a sponsor of a vaccine against a rare 
disease or condition may apply for grant support for clinical trials of the vaccine under 
the Office of Orphan Products Development Grant Program.  Designation as an orphan 
drug is not a requirement for consideration for support under this grant program.  Please 
note that a vaccine designated as an orphan product must be evaluated for safety and 
efficacy like any other vaccine (21 CFR 601.2(d)).  For more information, please contact 
the FDA Office of Orphan Products Development at 301-827-3666 or see: 
http://www.fda.gov/orphan/index.htm.  
9  Contains Nonbinding Recommendations 
 
VI.  REFERENCES  
 
1.  Guidance for Industry:  E8: General Considerations for Clinical Trials, December 1997, 
ICH. 
 
2.  Guidance for Industry:  E9: Statistical Principles for Clinical Trials, September 1998, 
ICH. 
 
3.  Guidance for Industry:  E10: Choice of Control Group and Related Issues in Clinical 
Trials, May 2001, ICH. 
 
4.  World Health Organization. WHO guidelines on nonclinical evaluation of vaccines.     
Annex 1.  WHO Technical Report Series. 2005; 927:31-63.  Available at  
http://www.who.int/biologicals/publications/trs/areas/vaccines/nonclinical_evaluation/en/ 
 
5.  Guidance for Industry:  Considerations for Developmental Toxicity Studies for 
Preventive and Therapeutic Vaccines for Infectious Disease Indications, February 2006. 
Available at 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformatio
n/Guidances/Vaccines/default.htm 
 
6.  Guidance for Industry:  Content and Format of Chemistry, Manufacturing and Controls 
Information and Establishment Description Information for a Vaccine or Related Product, 
January 1999. Available at 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformatio
n/Guidances/Vaccines/default.htm 
 
7.  Guidance for Industry:  Providing Clinical Evidence of Effectiveness for Human Drugs 
and Biological Products, May 1998. Available at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM078749.pdf 
 
8.  Final Rule, New Drug and Biological Drug Products: Evidence Needed to Demonstrate 
Effectiveness of New Drugs When Efficacy Studies are Not Ethical or Feasible,  
67 FR 37988, May 31, 2002. 
 
9.  Guidance for Industry:  Formal Meetings with Sponsors and Applicants for PDUFA   
Products, February 2000.  Available at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM079744.pdf 
 
10.  Final Rule, Human Subject Protection; Foreign Clinical Studies Not Conducted Under an 
Investigational New Drug Application, 73 FR 22800, April 28, 2008.   
 
11.  Guidance for Industry:  E6: Good Clinical Practice: Consolidated Guideline, May 1997, 
ICH.  
10  Contains Nonbinding Recommendations 
 
 
12.  Guidance for Industry:  E5: Ethnic Factors in the Acceptability of Foreign Clinical Data, 
June 2004, ICH.   
 
13.  Vaccines and Related Biological Products Advisory Committee meeting, May 26-27, 
1998. Available at http://www.fda.gov/ohrms/dockets/ac/98/transcpt/3422t1.pdf and 
http://www.fda.gov/ohrms/dockets/ac/98/transcpt/3422t2a.pdf 
 
14.  Pediatric Research Equity Act 2003, (Pub. L. No. 108-155) as reauthorized by the Food 
and Drug Amendments Act 2007, (Pub. L. No. 110-85). 
 
11