[Code of Federal Regulations]
[Title 21, Volume 7, Parts 600 to 799]
[Revised as of April 1, 2000]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR600.80]

[Page 13-17]
 
                        TITLE 21--FOOD AND DRUGS
 
          DEPARTMENT OF HEALTH AND HUMAN SERVICES--(Continued)
 
PART 600--BIOLOGICAL PRODUCTS: GENERAL--Table of Contents
 
               Subpart D--Reporting of Adverse Experiences
 
Sec. 600.80  Postmarketing reporting of adverse experiences.

    Source: 59 FR 54042, Oct. 27, 1994, unless otherwise noted.


    (a) Definitions. The following definitions of terms apply to this 
section:
    Adverse experience. Any adverse event associated with the use of a 
biological

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product in humans, whether or not considered product related, including 
the following: An adverse event occurring in the course of the use of a 
biological product in professional practice; an adverse event occurring 
from overdose of the product whether accidental or intentional; an 
adverse event occurring from abuse of the product; an adverse event 
occurring from withdrawal of the product; and any failure of expected 
pharmacological action.
    Blood Component. As defined in Sec. 606.3(c) of this chapter.
    Disability. A substantial disruption of a person's ability to 
conduct normal life functions.
    Life-threatening adverse experience. Any adverse experience that 
places the patient, in the view of the initial reporter, at immediate 
risk of death from the adverse experience as it occurred, i.e., it does 
not include an adverse experience that, had it occurred in a more severe 
form, might have caused death.
    Serious adverse experience. Any adverse experience occurring at any 
dose that results in any of the following outcomes: Death, a life-
threatening adverse experience, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, or a congenital anomaly/birth defect. Important 
medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse experience 
when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.
    Unexpected adverse experience: Any adverse experience that is not 
listed in the current labeling for the biological product. This includes 
events that may be symptomatically and pathophysiologically related to 
an event listed in the labeling, but differ from the event because of 
greater severity or specificity. For example, under this definition, 
hepatic necrosis would be unexpected (by virtue of greater severity) if 
the labeling only referred to elevated hepatic enzymes or hepatitis. 
Similarly, cerebral thromboembolism and cerebral vasculitis would be 
unexpected (by virtue of greater specificity) if the labeling only 
listed cerebral vascular accidents. ``Unexpected,'' as used in this 
definition, refers to an adverse experience that has not been previously 
observed (i.e., included in the labeling) rather than from the 
perspective of such experience not being anticipated from the 
pharmacological properties of the pharmaceutical product.
    (b) Review of adverse experiences. Any person having a biologics 
license under Sec. 601.20 of this chapter shall promptly review all 
adverse experience information pertaining to its product obtained or 
otherwise received by the licensed manufacturer from any source, foreign 
or domestic, including information derived from commercial marketing 
experience, postmarketing clinical investigations, postmarketing 
epidemiological/surveillance studies, reports in the scientific 
literature, and unpublished scientific papers. Licensed manufacturers 
are not required to resubmit to FDA adverse product experience reports 
forwarded to the licensed manufacturer by FDA; licensed manufacturers, 
however, must submit all followup information on such reports to FDA. 
Any person subject to the reporting requirements under paragraph (c) of 
this section shall also develop written procedures for the surveillance, 
receipt, evaluation, and reporting of postmarketing adverse experiences 
to FDA.
    (c) Reporting requirements. The licensed manufacturer shall report 
to FDA adverse experience information, as described in this section. The 
licensed manufacturer shall submit two copies of each report described 
in this section for nonvaccine biological products, to the Center for 
Biologics Evaluation and Research (HFM-210), Food and Drug 
Administration, 1401 Rockville Pike, suite 200 N., Rockville, MD 20852-
1448. Submit all vaccine adverse experience reports to: Vaccine Adverse 
Event Reporting System (VAERS), P.O. Box 1100, Rockville, MD 20849-1100.

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FDA may waive the requirement for the second copy in appropriate 
instances.
    (1)(i) Postmarketing 15-day ``Alert reports''. The licensed 
manufacturer shall report each adverse experience that is both serious 
and unexpected, whether foreign or domestic, as soon as possible but in 
no case later than 15 calendar days of initial receipt of the 
information by the licensed manufacturer.
    (ii) Postmarketing 15-day ``Alert reports''--followup. The licensed 
manufacturer shall promptly investigate all adverse experiences that are 
the subject of these postmarketing 15-day Alert reports and shall submit 
followup reports within 15 calendar days of receipt of new information 
or as requested by FDA. If additional information is not obtainable, 
records should be maintained of the unsuccessful steps taken to seek 
additional information. Postmarketing 15-day Alert reports and followups 
to them shall be submitted under separate cover.
    (iii) Submission of reports. The requirements of paragraphs 
(c)(1)(i) and (c)(1)(ii) of this section, concerning the submission of 
postmarketing 15-day Alert reports, shall also apply to any person whose 
name appears on the label of a licensed biological product as a 
manufacturer, packer, distributor, shared manufacturer, joint 
manufacturer, or any other participant involved in divided 
manufacturing. To avoid unnecessary duplication in the submission to FDA 
of reports required by paragraphs (c)(1)(i) and (c)(1)(ii) of this 
section, obligations of persons other than the licensed manufacturer of 
the final biological product may be met by submission of all reports of 
serious adverse experiences to the licensed manufacturer of the final 
product. If a person elects to submit adverse experience reports to the 
licensed manufacturer of the final product rather than to FDA, the 
person shall submit each report to the licensed manufacturer of the 
final product within 5 calendar days of receipt of the report by the 
person, and the licensed manufacturer of the final product shall then 
comply with the requirements of this section. Under this circumstance, a 
person who elects to submit reports to the licensed manufacturer of the 
final product shall maintain a record of this action which shall 
include:
    (A) A copy of all adverse biological product experience reports 
submitted to the licensed manufacturer of the final product;
    (B) The date the report was received by the person;
    (C) The date the report was submitted to the licensed manufacturer 
of the final product; and-
    (D) The name and address of the licensed manufacturer of the final 
product.
    (iv) Report identification. Each report submitted under this 
paragraph shall bear prominent identification as to its contents, i.e., 
``15-day Alert report,'' or ``15-day Alert report-followup.''
    (2) Periodic adverse experience reports. (i) The licensed 
manufacturer shall report each adverse experience not reported under 
paragraph (c)(1)(i) of this section at quarterly intervals, for 3 years 
from the date of issuance of the biologics license, and then at annual 
intervals. The licensed manufacturer shall submit each quarterly report 
within 30 days of the close of the quarter (the first quarter beginning 
on the date of issuance of the biologics license) and each annual report 
within 60 days of the anniversary date of the issuance of the biologics 
license. Upon written notice, FDA may extend or reestablish the 
requirement that a licensed manufacturer submit quarterly reports, or 
require that the licensed manufacturer submit reports under this section 
at different times than those stated. Followup information to adverse 
experiences submitted in a periodic report may be submitted in the next 
periodic report.
    (ii) Each periodic report shall contain:
    (A) A narrative summary and analysis of the information in the 
report and an analysis of the 15-day Alert reports submitted during the 
reporting interval (all 15-day Alert reports being appropriately 
referenced by the licensed manufacturer's patient identification number, 
adverse reaction term(s), and date of submission to FDA);
    (B) A form designated for Adverse Experience Reporting by FDA for 
each adverse experience not reported under

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paragraph (c)(1)(i) of this section (with an index consisting of a line 
listing of the licensed manufacturer's patient identification number and 
adverse reaction term(s)); and
    (C) A history of actions taken since the last report because of 
adverse experiences (for example, labeling changes or studies 
initiated).
    (iii) Periodic reporting, except for information regarding 15-day 
Alert reports, does not apply to adverse experience information obtained 
from postmarketing studies (whether or not conducted under an 
investigational new drug application), from reports in the scientific 
literature, and from foreign marketing experience.
    (d) Scientific literature. (1) A 15-day Alert report based on 
information from the scientific literature shall be accompanied by a 
copy of the published article. The 15-day Alert reporting requirements 
in paragraph (c)(1)(i) of this section (i.e., serious, unexpected 
adverse experiences) apply only to reports found in scientific and 
medical journals either as case reports or as the result of a formal 
clinical trial.
    (2) As with all reports submitted under paragraph (c)(1)(i) of this 
section, reports based on the scientific literature shall be submitted 
on the reporting form designated by FDA or comparable format as 
prescribed by paragraph (f) of this section. In cases where the licensed 
manufacturer believes that preparing the form designated by FDA 
constitutes an undue hardship, the licensed manufacturer may arrange 
with the Division of Biostatistics and Epidemiology (HFM-210) for an 
acceptable alternative reporting format.
    (e) Postmarketing studies. (1) Licensed manufacturers are not 
required to submit a 15-day Alert report under paragraph (c) of this 
section for an adverse experience obtained from a postmarketing clinical 
study (whether or not conducted under a biological investigational new 
drug application) unless the licensed manufacturer concludes that there 
is a reasonable possibility that the product caused the adverse 
experience.
    (2) The licensed manufacturer shall separate and clearly mark 
reports of adverse experiences that occur during a postmarketing study 
as being distinct from those experiences that are being reported 
spontaneously to the licensed manufacturer.
    (f) Reporting forms. (1) Except as provided in paragraph (f)(3) of 
this section, the licensed manufacturer shall complete the reporting 
form designated by FDA for each report of an adverse experience (FDA 
Form 3500A, or, for vaccines, a VAERS form; foreign events including 
those associated with the use of vaccines, may be submitted either on an 
FDA Form 3500A or, if preferred, on a CIOMS I form).
    (2) Each completed form should refer only to an individual patient 
or single attached publication.
    (3) Instead of using a designated reporting form, a licensed 
manufacturer may use a computer-generated form or other alternative 
format (e.g., a computer-generated tape or tabular listing) provided 
that:
    (i) The content of the alternative format is equivalent in all 
elements of information to those specified in the form designated by 
FDA; and
    (ii) the format is approved in advance by MEDWATCH: The FDA Medical 
Products Reporting Program; or, for alternatives to the VAERS Form, by 
the Division of Biostatistics and Epidemiology.
    (4) Copies of the reporting form designated by FDA (FDA-3500A) for 
nonvaccine biological products may be obtained from the Center for 
Biologics Evaluation and Research (address above). Additional supplies 
of the form may be obtained from the Consolidated Forms and Publications 
Distribution Center, 3222 Hubbard Rd., Landover, MD 20785. Supplies of 
the VAERS form may be obtained from VAERS by calling 1-800-822-7967.
    (g) Multiple reports. A licensed manufacturer should not include in 
reports under this section any adverse experience that occurred in 
clinical trials if they were previously submitted as part of the 
biologics license application. If a report refers to more than one 
biological product marketed by a licensed manufacturer, the licensed 
manufacturer should submit the report to the biologics license 
application for the product listed first in the report.

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    (h) Patient privacy. For nonvaccine biological products, a licensed 
manufacturer should not include in reports under this section the names 
and addresses of individual patients; instead, the licensed manufacturer 
should assign a unique code number to each report, preferably not more 
than eight characters in length. The licensed manufacturer should 
include the name of the reporter from whom the information was received. 
The names of patients, health care professionals, hospitals, and 
geographical identifiers in adverse experience reports are not 
releasable to the public under FDA's public information regulations in 
part 20 this of chapter. For vaccine adverse experience reports, these 
data will become part of the CDC Privacy Act System 09-20-0136, 
``Epidemiologic Studies and Surveillance of Disease Problems.'' 
Information identifying the person who received the vaccine or that 
person's legal representative will not be made available to the public, 
but may be available to the vaccinee or legal representative.
    (i) Recordkeeping. The licensed manufacturer shall maintain for a 
period of 10 years records of all adverse experiences known to the 
licensed manufacturer, including raw data and any correspondence 
relating to the adverse experiences.
     (j) Revocation of biologics license. If a licensed manufacturer 
fails to establish and maintain records and make reports required under 
this section with respect to a licensed biological product, FDA may 
revoke the biologics license for such a product in accordance with the 
procedures of Sec. 601.5 of this chapter.
    (k) Exemptions. Manufacturers of the following listed products are 
not required to submit adverse experience reports under this section:
    (1) Whole blood or components of whole blood.
    (2) In vitro diagnostic products, including assay systems for the 
detection of antibodies or antigens to retroviruses. These products are 
subject to the reporting requirements for devices.
    (l) Disclaimer. A report or information submitted by a licensed 
manufacturer under this section (and any release by FDA of that report 
or information) does not necessarily reflect a conclusion by the 
licensed manufacturer or FDA that the report or information constitutes 
an admission that the biological product caused or contributed to an 
adverse effect. A licensed manufacturer need not admit, and may deny, 
that the report or information submitted under this section constitutes 
an admission that the biological product caused or contributed to an 
adverse effect. For purposes of this provision, this paragraph also 
includes any person reporting under paragraph (c)(1)(iii) of this 
section.

[59 FR 54042, Oct. 27, 1994, as amended at 62 FR 34168, June 25, 1997; 
62 FR 52252, Oct. 7, 1997; 63 FR 14612, Mar. 26, 1998; 64 FR 56449, Oct. 
20, 1999]