0458 AdverseExperience21cfr600 80

Food and Drug Administration, HHS

§ 600.80
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
§ 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

(f) Bring to the attention of the manufacturer any fault observed in the
course of inspection in location, construction, manufacturing methods, or
administration of a licensed establishment which might lead to impairment
of a product,
(g) Inspect and copy, as circumstances may require, any records
required to be kept pursuant to § 600.12,
(h) Certify as to the condition of the
establishment and of the manufacturing methods followed and make recommendations as to action deemed appropriate with respect to any application for license or any license previously issued.
[38 FR 32048, Nov. 20, 1973, as amended at 49
FR 23833, June 8, 1984; 55 FR 11013, Mar. 26,
1990]

Subpart D—Reporting of Adverse
Experiences
SOURCE: 59 FR 54042, Oct. 27, 1994, unless
otherwise noted.

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

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§ 600.80

21 CFR Ch. I (4–1–04 Edition)

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.
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

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Food and Drug Administration, HHS

§ 600.80

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
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:

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§ 600.81

21 CFR Ch. I (4–1–04 Edition)

(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.
(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 § 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]

§ 600.81

Distribution reports.

The licensed manufacturer shall submit information about the quantity of

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