Guidance for Industry 
 
FDA Review of Vaccine Labeling 
Requirements for Warnings, Use 
Instructions, and Precautionary 
Information 
 
 
 
 
FDA is issuing this guidance for immediate implementation in accordance with 21 CFR 
10.115(g)(4)(i).  Submit 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 the title of this guidance. 
 
Additional copies of this guidance are available from the Office of Communication, Training and 
Manufacturers Assistance (HFM-40), 1401 Rockville Pike, 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 Bette Goldman at 301-827-0655.  
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research 
September 2004  Contains Nonbinding Recommendations 
 
 
Table of Contents 
 
 
I.  PURPOSE.........................................................................................................................1 
II.  INTRODUCTION............................................................................................................1 
III.  FDAS PROCESS FOR VACCINE LABELING REVIEW........................................2 
A.  Pre-Approval Review of Labeling......................................................................2 
B.  Post-Approval Surveillance................................................................................3 
IV.  FDAS NCVIA VACCINE LABELING REVIEW......................................................3 
A.  Legislative Background.......................................................................................3 
B.  FDAS Process for Conducting the NCVIA Labeling Review.........................4 
1.  Preparation of Summaries of Important Information.................................4 
2.  Public Participation....................................................................................5 
V.  CONCLUSION................................................................................................................6 
 
 
 
  i  
 
Guidance for Industry 
 
FDA Review of Vaccine Labeling Requirements for Warnings, Use 
Instructions, and Precautionary Information  
 
 
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.  PURPOSE 
 
This guidance document is meant to inform you, vaccine manufacturers, medical practitioners, 
and consumers, of the type of data that we, FDA, examine when determining the adequacy of 
vaccine labeling1 by providing an overview of the vaccine labeling review process and 
describing our review of childhood vaccine labeling under section 314 of the National Childhood 
Vaccine Injury Act (NCVIA).2  The processes described herein represent current FDA practices 
and do not represent any new interpretation of existing labeling statutes, regulations, or 
guidances. 
 
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.  INTRODUCTION 
 
FDA  routinely assesses the warnings, use instructions, and precautionary information provided 
for licensed vaccines.  Based on its surveillance of adverse event reporting and other data 
sources, we review the adequacy of vaccine labeling and, if necessary, communicate our findings 
to manufacturers.  This guidance document provides FDA's current thinking about its 
surveillance and review of vaccine labeling.  
 
The review of vaccine labeling completed by FDA pursuant to section 314 of the NCVIA 
provides a useful description of some of the methods we use to evaluate the adequacy of the 
warnings, use instructions, and precautionary information found in vaccine package inserts.  
                                                 
1 The term "labeling," as defined in 21 U.S.C.  321(m), means all labels and other written, printed, or graphic 
matter upon any article or any of its containers or wrappers, or accompanying such article and, therefore, includes 
any package inserts or information sheets that accompany vaccine products.  
2 Pub. L. No. 99-660, 100 Stat. 3755, codified at 42 U.S.C.  300aa-1 et seq. 
1   
 
Secton 314 of the NCVIA required FDA to review the warnings, use instructions, and 
precautionary information distributed with each vaccine listed in section 2114 of the Public 
Health Service Act (PHS Act)3 at the time of the NCVIA's passage.  The statute also required 
FDA to determine whether such warnings, instructions, and information "adequately warn health 
care providers of the nature and extent of the dangers posed by such vaccines."4  If such 
information was found to be inadequate, section 314 of the NCVIA mandated that manufacturers 
be required to revise and reissue such warnings, use instructions and precautionary information 
as expeditiously as practical.   
 
FDA continues to engage in an ongoing, case-by-case review of all vaccine labeling and 
routinely requires revision of labeling that is found to be inadequate to warn health care 
providers of the risks associated with the use of a particular vaccine. 
 
III.  FDAS PROCESS FOR VACCINE LABELING REVIEW 
 
The labeling requirements for biological products are found in several sections of the Federal 
Food, Drug, and Cosmetic Act (FDCA) and the PHS Act, including:  Sections 201, 502, and 503 
of the FDCA, and section 351 of the PHS Act.  In addition to the statutory provisions, FDAs 
regulations on labeling requirements, including the content and format requirements for vaccine 
labeling, are found primarily in 21 CFR Parts 201 and 601. 
 
Pursuant to 21 CFR 201.57(d), labeling must describe contraindications (situations in which the 
drug should not be used because the risk of use clearly outweighs any possible benefit).  The 
warning section of labeling, defined in section 201.57(e), requires, among other things, a 
description of serious adverse reactions, potential safety hazards, steps that should be taken in 
the occurrence of a serious adverse reaction and potential safety hazard, and limitations in use 
imposed by them.  
 
A.  Pre-Approval Review of Labeling 
 
Under 21 CFR 601.2(a), manufacturers must submit proposed vaccine labeling to FDA as 
part of a biological license application (BLA).  In addition, changes to existing vaccine 
labeling requires FDA review pursuant to 21 CFR 601.12(f).  Most such changes require 
a BLA supplement (BLS) and transmittal Form FDA 2567.  In its review, FDA 
determines whether the information presented in the labeling is scientifically accurate, 
conforms to regulatory requirements set out in 21 CFR 201.56 and 201.57, and includes 
requested revisions. 
 
An important part of vaccine labeling is the package insert.  FDA reviews the entire 
package insert to determine whether it is adequate.  If we conclude that a proposed 
vaccine package insert does not contain adequate warnings, use instructions, and 
precautionary information, we communicate such findings to the manufacturer as soon as 
is practicable.  When FDA concludes that a vaccine labels warnings, use instructions, 
                                                 
3 See 42 U.S.C.  300aa-14. 
4 See 42 U.S.C.  300aa-1 note. 
2   
 
and precautionary information have been sufficiently revised to include current 
information regarding the nature and extent of the dangers posed by such vaccines, FDA 
formally approves the final draft labeling as described in 21 CFR 601.2 and 601.12(f). 
 
B.  Post-Approval Surveillance 
 
FDA takes into account various sources of information during our surveillance and 
review of vaccine labeling requirements for warnings, use instructions, and precautionary 
information, including: 
 
  The existing labeling requirements listed under 21 CFR 201.56 and 201.57; 
  Epidemiological information contained in Morbidity and Mortality Weekly 
Reports (MMWR), published by the Centers for Disease Control and Prevention 
(CDC);5 
  Reports in the medical literature; and  
  Summaries from the Vaccine Adverse Event Reporting System (VAERS). 
When new information on a vaccines safety and efficacy becomes available after 
licensure, FDA reviews the data and determines whether package inserts and other 
labeling should be revised to include this new information.  FDA notifies manufacturers 
if their package inserts do not reflect currently available information regarding the 
warnings, use instructions and precautionary information.  In such a case, FDA also 
typically recommends that appropriate revision is necessary. 
 
IV.  FDAS NCVIA VACCINE LABELING REVIEW 
 
A.  Legislative Background  
 
Under section 314 of the NCVIA, FDA was required to determine whether the warnings, 
use instructions and precautionary information for certain enumerated childhood vaccines 
were adequate to warn health care providers of the nature and extent of the risks posed by 
such vaccines.  The NCVIA limited this requirement to childhood vaccines listed in the 
Vaccine Injury Table (VIT) established in section 2114 of the PHS Act.6  If FDA 
determined that any such warnings, use instructions or precautionary information were 
inadequate, then manufacturers were required to revise and reissue such warnings, use 
instructions or precautionary information as expeditiously as practical. 
 
On June 13, 1988, the Secretary delegated authority to implement section 314 of the 
NCVIA to the Assistant Secretary for Health (ASH).7  On September 16, 1988, the ASH 
delegated authority to implement section 314 of the NCVIA to the Commissioner of 
                                                 
5 See http://www.cdc.gov/mmwr/. 
6 See 42 U.S.C.  300aa-14. 
7 53 Fed. Reg. 22054 (June 13, 1988). 
3   
 
Food and Drugs.8  On April 1, 1993, FDA delegated to the Center for Biologics 
Evaluation and Research authority to implement section 314 of the NCVIA.9 
 
B.  FDAS Process for Conducting the NCVIA Labeling Review 
 
FDA conducted its review of vaccine labeling under section 314 of the NCVIA through a 
process that involved extensive opportunities for public comment on childhood vaccine 
labeling.  By applying existing drug labeling regulations (e.g., 21 CFR 201.56 and 
201.57), current labeling as supplied by the manufacturer, as well as a survey of medical 
practitioners, FDA created draft Summaries of Important Information (SII) for each 
applicable vaccine listed in section 2114s Vaccine Injury Table (VIT) and distributed 
them to the appropriate manufacturers on March 3, 1992. 
 
On July 31, 1992, FDA announced the creation of a public docket and scheduled a public 
meeting to seek comments on manufacturers' and FDA's proposed revisions to the 
package inserts, which had been made available for public examination.10  At that time, 
FDA also made available the respective vaccines' most recently approved package 
inserts, manufacturers' proposed revised drafts of package inserts, as well as FDA's 
comments on the inserts.  FDA established time frames for completion of its review and 
response to public comments.11  Subsequently, FDA reviewed each manufacturers 
proposed labeling changes, and, after considering the public record, approved labeling 
changes for the listed childhood vaccines, thus determining the revised labeling to be 
adequate to warn health care providers of the nature and extent of the risks posed by such 
vaccines.  
 
Throughout its review process, FDA consulted the Advisory Commission on Childhood 
Vaccines (ACCV) to assess the warnings, use instructions and precautionary information 
issued for applicable childhood vaccines.  The NCVIA mandated creation of the ACCV 
to provide expert advice to the Secretary about, among other things, the implementation 
of the statute.  The ACCV also makes recommendations regarding changes to the VIT 
and surveys Federal, State and local information regarding childhood vaccine associated 
injuries.12  FDA representatives attended ACCV meetings and briefed the ACCV on the 
labeling review. 
 
1.  Preparation of Summaries of Important Information 
 
As discussed above, FDA prepared an SII for each vaccine listed in the VIT to 
serve as a guide to manufacturers when revising package inserts.  Creation of the 
SIIs also facilitated harmonization of package inserts for similar vaccines 
produced by different manufacturers.  In the SIIs, FDA recommended the location 
                                                 
8 53 Fed. Reg. 36127 (September 16, 1988). 
9 58 Fed. Reg. 17105 (April 1, 1993). 
10 57 Fed. Reg. 33915 (July 31, 1992).  As discussed below, this public meeting was held on September 18, 1992. 
11 Id. 
12 See 42 U.S.C.  300aa-19. 
4   
 
and content of specific package insert sections and subsections and in several 
instances, suggested precise wording.13 
 
On March 3, 1992, FDA sent to the respective childhood vaccine manufacturers 
copies of the draft SIIs for each vaccine listed in the VIT.  FDA notified 
manufacturers of the workshop planned for September 18, 1992, and requested 
them to submit to FDA suggested revisions of draft SIIs.  FDA presented revised 
draft SIIs for public review prior to the workshop and acceptepted comments filed 
to Docket No. 91N-0494.14  The docket included the following:  (1) package 
inserts most recently approved by FDA; (2) manufacturers' draft package inserts 
with FDA's comments, if revisions were still pending as of July 1992; or (3) the 
most recently approved package inserts and FDA's comments, if revised drafts 
had not been received by July 1992; and (4) copies of the SIIs.   
 
As the basis for these draft SIIs, FDA used the labeling requirements listed under 
21 CFR 201.56 and 201.57, the Advisory Committee on Immunization Practices' 
(ACIP) "Recommendations & Reports, and approved package inserts.  FDA also 
referred to reports prepared by the Panel on the Review of Bacterial Vaccines and 
Toxoids15 and the Panel on the Review of Viral Vaccines and Rickettsia,16 
epidemiological information from MMWR, literature references, and summaries 
from VAERS. 
 
2.  Public Participation 
 
As noted previously, FDA took into account the views of several public panels 
during the review of childhood labeling.  The Panel on the Review of Bacterial 
Vaccines and Toxoids and the Panel on the Review of Viral and Rickettsial 
Vaccines conducted separate reviews regarding the safety, efficacy, and labeling 
of bacterial vaccines, toxoids with standards of potency, antitoxins, and immune 
globulins; and viral and rickettsial vaccines, respectively.  Each panels review 
resulted in a proposed order that was published in the Federal Register.  Both 
panels' reports recommended that information in the package insert be presented 
in a clear, unambiguous and accurate manner.  The panels also reviewed FDA's 
requirements for package inserts and suggested the types of information that 
should be included.  FDA considered the recommendations of both panels and 
incorporated many of them into the relevant SIIs. 
                                                 
13 Following is a list of the vaccines for which SIIs were prepared:  (1) Diphtheria Toxoid Adsorbed; (2) Diphtheria 
and Tetanus Toxoids Adsorbed; (3) Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed; (4) 
Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed; (5) Measles and Mumps Virus Vaccine 
Live; (6) Measles and Rubella Virus Vaccine Live; (7) Measles, Mumps and Rubella Virus Vaccine Live; (8) 
Measles Virus Vaccine Live; (9) Mumps Virus Vaccine Live; (10) Pertussis Vaccine Adsorbed; (11) Poliovirus 
Vaccine Inactivated; (12) Poliovirus Vaccine Live Oral Trivalent; (13) Rubella and Mumps Virus Vaccine Live; 
(14) Rubella Virus Vaccine Live; (15) Tetanus and Diphtheria Toxoids Adsorbed (for Adult Use); (16) Tetanus 
Toxoid; (17) Tetanus Toxoid Adsorbed. 
14 See 57 Fed. Reg. 33915 (Jul. 31, 1992). 
15 See 50 Fed. Reg. 51002 (Dec. 13, 1985). 
16 See 45 Fed. Reg. 25652 (Apr. 15, 1980). 
5   
 
 
At the September 1992 public workshop, FDA described its labeling review 
process and presented the reviews it had conducted for each childhood vaccine 
pursuant to section 314 of the NCVIA.  Several groups presented comments, 
including:  Government agencies such as the National Institutes of Health and the 
CDC; advisory bodies (including ACIP, ACCV, the American Academy of 
Pediatrics, and the National Vaccine Advisory Committee), and the Vaccine and 
Related Biological Products Advisory Committee; manufacturers; and interested 
members of the public.  FDA considered these presentations and submissions 
made during the workshop, comments submitted to the Docket, as well as direct 
correspondence from manufacturers and other interested members of the public.  
FDA reviewed the revised labeling of the childhood vaccines enumerated in the 
VIT and determined that the labeling, as revised, contained adequate warnings. 
 
V.  CONCLUSION 
 
As a result of the public process utilized to implement section 314 of the NCVIA, FDA 
determined that the warnings, use instructions, and precautionary information distributed with 
each vaccine set forth in section 2114 of the PHS Act adequately warned health care providers of 
the nature and extent of the dangers posed by such vaccines.  FDA has reviewed the labeling of 
all vaccines originally listed in the VIT as well as those subsequently added to the table. 
 
FDAs continuing review of warnings and precautions and use instructions sections of the label 
helps assure that labels in distribution are adequate to inform health care providers of the risks of 
vaccines.  FDA continues to review vaccine labeling, taking into account timely information 
provided through, among other things, recommendations and reports of the ACIP, 
epidemiological information contained in the MMWR, reports in the medical literature; and 
summaries from VAERS.  
6