[Federal Register Volume 59, Number 207 (Thursday, October 27, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-26482]


[[Page Unknown]]

[Federal Register: October 27, 1994]


      
_______________________________________________________________________

Part II





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



_______________________________________________________________________



21 CFR Part 600



Adverse Experience Reporting Requirements For Licensed Biological 
Products; Final Rule
DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 600

[Docket No. 85N-0506]
RIN 0905-AB53

 

Adverse Experience Reporting Requirements for Licensed Biological 
Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is amending the 
regulations to require manufacturers of licensed biological products 
(hereinafter referred to as licensed manufacturers) to report to FDA 
within 15 working days all adverse experiences associated with the use 
of a biological product that are both serious and unexpected; any 
significant increase in the frequency of a serious, but expected 
adverse experience; periodically, all other adverse experiences; and 
product distribution and disposition data. FDA is taking this action to 
provide a mechanism under which licensed manufacturers would inform the 
agency, on a timely basis, of any unanticipated safety problems with 
marketed biological products.

EFFECTIVE DATE: This regulation is effective December 27, 1994.

ADDRESSES: Copies of Form FDA-3500A may be obtained from the Center for 
Biologics Evaluation and Research (HFM-210), Food and Drug 
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-
1448. Additional copies of the form may be obtained from the 
Consolidated Forms and Publications Distribution Center, 3222 Hubbard 
Rd., Landover, MD 20785. Copies of the VAERS form may be obtained from 
the Vaccine Adverse Event Reporting System (VAERS) by calling 1-800-
822-7967.
    All reports required by this regulation pertaining to nonvaccine 
biological products should be sent to the Center for Biologics 
Evaluation and Research (address above). All reports required by this 
regulation pertaining to vaccines should be sent to VAERS, P.O. Box 
1100, Rockville, MD 20849-1100.

FOR FURTHER INFORMATION CONTACT: Paula S. McKeever, Center for 
Biologics Evaluation and Research (HFM-635), Food and Drug 
Administration, 1401 Rockville Pike, Rockville, MD 20852-1448, 301-594-
3074.
 SUPPLEMENTARY INFORMATION: 

I. Introduction

    In the Federal Register of April 24, 1979 (44 FR 24233), FDA made 
available for public comment a draft proposed regulation that would 
require the maintenance of records and submission of reports of adverse 
experiences involving licensed biological products. After evaluating 
the comments received and analyzing other information, FDA issued a 
proposed regulation (hereinafter referred to as the 1990 proposal) and 
notice of availability of a draft guideline in the Federal Register of 
March 29, 1990 (55 FR 11611 and 11655, respectively). The 1990 proposal 
was to require all manufacturers of licensed biological products to 
submit the following reports to FDA: (1) Alert reports within 15 
working days of receipt of adverse experiences associated with the use 
of a licensed biological product that are both ``serious and 
unexpected,'' and of any ``significant increase in frequency'' of an 
adverse experience that is both ``serious and unexpected;'' and (2) 
periodic reports of all adverse experiences, including both serious and 
nonserious adverse experiences, that are not included in a 15-day Alert 
report. The statutory authority for promulgating these regulations was 
described in detail in the preamble to the 1990 proposal (55 FR 11611 
at 11613). The agency provided 60 days for interested persons to submit 
written comments on the 1990 proposal.
    Prior to promulgation of this final rule, only adverse experiences 
associated with certain childhood vaccines (see 53 FR 10565, April 1, 
1988) and fatalities resulting from blood collection or transfusion 
(Sec. 606.170 (21 CFR 606.170)) were required to be reported to FDA for 
biological products. Although many manufacturers of other types of 
biological products voluntarily submit adverse experience reports to 
FDA, there has not necessarily been consistent or complete reporting 
from all licensed manufacturers.
    In the Federal Register of June 3, 1993 (58 FR 31596), FDA issued a 
notice announcing the availability of a new form for reporting adverse 
events and product problems with human drug products, biologic 
products, medical devices, special nutritional products, and other 
products regulated by FDA. One version of the form (FDA Form 3500) was 
made available for use by health professionals for voluntary reporting; 
the other version of the form (FDA Form 3500A) was made available for 
use by user facilities, distributors, and manufacturers for reporting 
that is required by statute or by FDA regulation. The new form is part 
of an FDA MEDWATCH program which is intended to consolidate and 
simplify reporting of adverse events and product problems for all FDA-
regulated products.
    Many of the comments received in response to the 1990 proposal, 
while having merit, if implemented would require changes to the 
regulations governing the reporting of adverse experiences for biologic 
products which would cause these requirements to diverge significantly 
from the requirements and reporting program for drugs as provided in 
Secs. 310.305 and 314.80 (21 CFR 310.305 and 314.80)). Such a 
divergence would be contrary to the MEDWATCH program which is intended, 
in part, to enhance consistency in the reporting and collection of 
information on adverse experiences related to FDA-regulated products. 
Rather than making such significant changes in this final rule, FDA is 
issuing a notice of proposed rulemaking elsewhere in this issue of the 
Federal Register which would appropriately amend the requirements in 
Secs. 310.305, 312.32 (21 CFR 312.32), and 314.80 for reporting of 
adverse experiences related to human drugs and the requirements in this 
final rule (Secs. 600.80 and 600.81) for reporting adverse experiences 
related to biological products. Later in this preamble, in response to 
a number of public comments which request significant changes to the 
regulations, FDA refers to the proposed rule which provides a more 
substantial discussion of the issues involved.
    Elsewhere in this issue of the Federal Register, FDA is also 
announcing the availability of a guideline entitled ``The Guideline for 
Adverse Experience Reporting for Licensed Biological Products'' 
(referred to as ``guideline'' in this final rule). The guideline 
discusses in detail the reports required by this rule, and provides 
guidance concerning some appropriate means of meeting the reporting 
requirements.

II. Highlights of the Final Rule

    This final rule establishes procedures under Secs. 600.80 and 
600.81 for licensed manufacturers to inform FDA about adverse 
experiences that are associated with the use of a licensed biological 
product and about biological product distribution. These procedures are 
intended to support the agency's efforts to protect the public safety 
by providing the agency with the information necessary for effective 
postmarket surveillance of biological products. This final rule 
requires licensed manufacturers of biological products to submit 
various reports to the agency and specifies the timeframes for 
submission of these reports. The reports are: (1) Fifteen-day Alert 
reports, (2) increased frequency alert reports, (3) periodic adverse 
experience reports and (4) distribution reports. The timeframes and 
contents of these adverse experience reports were the subject of 
numerous comments, which are discussed below. In addition to the 
reporting requirements, the final rule specifies record-keeping 
requirements, provides for exemptions of two categories of biological 
products, provides a disclaimer regarding causality, and provides for 
license revocation if licensed manufacturers fail to establish and 
maintain records and submit the required reports. In addition, this 
final rule provides procedures, under Sec. 600.90, for applying for 
waivers from any of the reporting requirements.
    The requirements in this final rule are consistent with existing 
requirements in Secs. 314.80 and 314.81 (21 CFR 314.81) regarding 
approved new drug products, except when differences are necessary to 
accommodate laws, terminology, procedures, and characteristics unique 
for biological products.

A. Scope

    The new procedures apply to all licensed manufacturers of 
biological products and any person, other than the licensed 
manufacturer of a biological product, whose name appears on the label 
of a licensed biological product as a manufacturer, packer, 
distributor, shared manufacturer, joint manufacturer, or a participant 
in divided manufacturing.

B. Format

    The format of Sec. 600.80 has been revised from what was proposed 
to be consistent with Sec. 314.80. FDA believes that the revised format 
will reduce the burden for manufacturers following the regulations for 
both drug and biological products.

III. Comments on the Proposed Rule and FDA Responses

    FDA received 15 letters of comment on the proposed rule. Most 
letters contained numerous comments on various areas of the proposed 
rule. Four of these comments supported codification of the reporting 
requirements for adverse experiences associated with biological 
products. Other comments either addressed particular paragraphs in the 
proposed regulation or dealt with the effect of the regulation on a 
particular type of biological product. In addition to the amendments 
discussed below, editorial changes were made throughout the rule. A 
summary of these comments and the agency's responses follow:

A. General Comments

1. Consistency With Section 314.80
    Two comments on Sec. 600.80 recognized the reporting issues unique 
to biological products and were supportive of both the 1990 proposal 
and the draft guideline for recognizing the differences between drugs 
and biological products. In contrast, four comments requested that FDA 
not deviate from the rules and guidelines applicable to drugs and 
requested that the regulations for reporting adverse experiences for 
biological products mirror the regulations for drugs.
    FDA intends these rules to be consistent with other agency 
initiatives and requirements regarding adverse experience reporting for 
drugs and medical devices wherever practical. This is demonstrated by 
the new adverse experience reporting Form FDA-3500A, which, with the 
exception of adverse experience reports associated with vaccines, is to 
be used for reporting of adverse events associated with drugs, 
biologics, and certain other products regulated by FDA. The final rule 
contains requirements unique to biological products only when necessary 
to accommodate the laws applicable only to biological products, such as 
vaccines, or to accommodate special characteristics of biological 
products.
2. Agency Review of Adverse Experience Reports
    One comment requested that the unit of FDA responsible for 
receiving adverse experience reports for drugs continue to be 
responsible for the adverse experiences for biologics to assure 
consistency of interpretation of the regulations and dissemination of 
information within FDA.
    The agency intends to maintain consistency between the Center for 
Biologics Evaluation and Research (CBER) and the Center for Drugs 
Evaluation and Research (CDER) in the interpretation of the 
regulations, especially with respect to terminology. A separate unit 
was created with the responsibilities related to postmarketing 
surveillance of licensed biological products because the agency 
recognizes that these products can present different safety concerns 
due to inherent differences in the products. In addition, the National 
Childhood Vaccine Injury Act of 1986 (NCVIA) mandated specific 
reporting requirements for manufacturers of certain vaccines and for 
health care providers administering those vaccines. VAERS was 
established to receive these required reports, as well as reports on 
other vaccines. The VAERS program is administered jointly by FDA and by 
the Centers for Disease Control and Prevention (CDC) and replaces 
previous vaccine reporting systems within both agencies. Section 
600.80(c) has been amended in the final rule to reflect the change of 
address for submitting reports due to the reorganization and relocation 
of CBER.
3. Clarification of Overlap Between the Vaccine Adverse Event Reporting 
System and Sec. 600.80
    Comments were received requesting clarification of overlap between 
the requirements of NCVIA and the regulations.
     NCVIA created a new Title XXI of the Public Health Service Act 
(the PHS Act). Section 2125 of the PHS Act (42 U.S.C. 300aa-25) 
requires health care providers who administer certain vaccines and 
manufacturers of the vaccines to report specified adverse experiences, 
occurring within specified time intervals after administration of the 
vaccines. These adverse experience reports are submitted to VAERS, 
which is jointly managed by FDA and CDC and became operational on 
November 1, 1990. A form VAERS-1 was developed for these reports. When 
the requirements set forth in both Sec. 600.80 and NCVIA necessitate 
reporting of an adverse event, licensed manufacturers of vaccines are 
not required to submit duplicate reports to VAERS and FDA. Submission 
of the report to VAERS is sufficient. However, licensed manufacturers 
of vaccines must comply with the regulations in Sec. 600.80. Therefore, 
any requirements in these regulations that are in addition to those 
specified in the NCVIA must be satisfied. For example, although NCVIA 
does not specify the time periods for submission of adverse experience 
reports, the time periods set forth in Sec. 600.80 apply to reports 
being submitted to VAERS.
4. Requests for Waivers
    Six comments requested waivers from the reporting requirements for 
specific types of adverse experiences or for certain categories of 
biological products. These requests for waivers were with respect to 
parts or all of the requirements of proposed Sec. 600.80. In addition, 
one comment requested that the final rule specify the provisions for 
requesting a waiver.
    The agency agrees that the provisions for a waiver should be 
specified in the final rule and has added a new Sec. 600.90 describing 
the procedures for requesting a waiver. Section 600.90 is similar to 
Sec. 314.90 (21 CFR 314.90), the provision for waivers for drugs or 
antibiotics. Manufacturers and other interested persons should submit 
requests for waivers as provided in Sec. 600.90 of the final rule.
5. Economic Assessment
    One comment requested clarification of FDA's estimate of the cost 
of complying with the reporting requirements of the proposed rule of 
approximately $255,490. The company estimates that its cost in labor 
and overhead would be approximately $40,000. In contrast, another 
comment stated that the company did not anticipate that this reporting 
requirement would significantly alter the manner in which companies 
would share their postmarketing information with FDA.
    The agency's assessment of cost was made over 4 years ago when both 
the number of approved biological products was fewer and costs somewhat 
less. In addition, the agency's figures did not take into account 
overhead and other costs associated with basic manufacturing practices. 
Every responsible manufacturer and distributor, regardless of the type 
of product manufactured, implements a means to receive inquiries about 
the quality and adverse effects of its products as good manufacturing 
practices and as an accepted part of doing business. Therefore, this 
cost has not been included in assessing the cost of this regulation. 
The costs assessed for this regulation only related to the specific 
costs incurred by the requirements in the regulation which are in 
addition to customary business practice. The costs of the regulation 
are for preparation of the specific reports and analyses required by 
the regulation and do not include the normal operating and overhead 
costs of doing business. The revised economic assessment is discussed 
at the end of this preamble.

B. Definitions Section 600.80(a)

1. Adverse Experience
    Four comments requested clarification of the definition of 
``adverse experience'' in proposed Sec. 600.80(a), particularly the 
phrase ``significant failure of expected pharmacological action * * * 
whether or not considered product related.'' One comment stated that 
the word ``significant'' has one meaning in the definition of ``adverse 
experience'' and another statistical meaning in the usage of the term 
``increased frequency'' in proposed Sec. 600.80(c)(1)(ii) and requested 
that the word be used consistently with the same meaning throughout the 
regulation. Another comment requested a definition of ``significant 
failure'' as used in the definition of adverse experience. One comment 
requested that the definition be amended to require reporting of 
changes in failure rates instead of any significant failure. One 
comment gave the following examples of incidents that would be 
considered an adverse experience with any significant failure: a 
patient who dies of acute myocardial infarction in spite of 
thrombolytic therapy; or a patient who dies of congestive heart failure 
despite diuretic therapy, i.e., deaths from progression of the 
indicated disease. One comment stated that it concurs with the agency's 
definition of ``adverse experience'' because it does not include ``loss 
of response'' as an adverse experience. The comment goes on to state 
that loss of immunity over time from a vaccine is not logically an 
adverse event.
    The agency agrees that the word ``significant'' when used in this 
context is a source of confusion and ambiguity. To eliminate this 
source of confusion and to encourage the reporting of all adverse 
experiences, FDA revised Sec. 314.80 to delete the word ``significant'' 
from the definition of ``adverse experience'' in the reporting 
requirements for drugs (see 57 FR 17950, April 28, 1992) and is 
revising the definition of ``adverse experience'' in this final rule by 
deleting the word ``significant.''
    The agency is retaining the proposed language in the definition of 
``adverse experience'' instead of adopting the suggestion to require 
reporting only of changes in failure rate because a ``change in failure 
rate'' can only be determined retrospectively. A change in failure rate 
is to be reported in an increased frequency report; however, a failure 
of expected pharmacological action that causes a serious and unexpected 
adverse experience in humans should be reported within 15 days 
regardless of the rate of such reports.
    The agency believes that the examples given may or may not indicate 
a ``failure of expected pharmacological action.'' For example, patients 
with congestive heart failure often have irreparable kidney damage 
which even the most potent diuretics cannot overcome. In such a 
situation congestive heart failure would not be a failure of expected 
pharmacologic action. However, the extent of pre-existing kidney damage 
and the degree to which kidney failure may be expected would be 
demonstrable through kidney function tests prior to medication. 
Therefore, FDA is not amending the definition of adverse experience as 
requested.
    The agency agrees partially with the comment regarding ``loss of 
response.'' If loss of immunity over time is the expected pharmacologic 
action of the vaccine, then it is not an adverse experience. If loss of 
immunity is due to a patient's compromised immune system, this also 
would not be considered an adverse experience. However, loss of 
immunity due to an unexpected failure of the pharmacologic action of 
the vaccine, thereby leaving recipients susceptible to a communicable 
disease, is an adverse experience and should be reported. The guideline 
points out that for purposes of adverse events reporting, ``lack of 
effect'' is generally synonymous with ``failure to produce the expected 
pharmacologic action.'' Certain products are indicated for immunization 
through a recommended course of several doses to achieve a specified 
level of antibody titer to provide seroprotection. In this case, ``lack 
of effect'' is synonymous with ``failure to produce the expected 
pharmacologic action'' only when adequate seroconversion is not 
achieved following the final dose.
2. Blood Components
    One comment noted that the language in the proposed 
Sec. 600.80(l)(1) and preamble refers to blood components yet the 
section of the CFR upon which the exemption is predicated 
(Sec. 606.170) refers to blood products. The comment specifically asked 
whether albumin and immunoglobulin are exempt from the rule and 
requested clarification of the meaning of blood component in 
Sec. 600.80(a).
    FDA is clarifying the regulations by adding in Sec. 600.80(a) of 
the final rule a reference to 21 CFR 606.3(c), which defines a ``Blood 
Component'' as ``that part of a single-donor unit of blood separated by 
physical or mechanical means.'' The exemption in Sec. 600.80(l), for 
reporting adverse experiences associated with blood components, does 
not include products derived from pooled blood such as albumin or 
immunoglobulin. Therefore, albumin and immunoglobulin are biological 
products subject to this rule.
    In a future issue of the Federal Register FDA intends to propose 
revisions to Sec. 606.170, concerning reports related to blood 
collection or transfusion.
3. Disability
    Two comments requested that a definition for ``disability'' be 
included in Sec. 600.80(a) as the phrase ``permanently disabling'' is 
used in the definition of ``serious.''
    The agency agrees that the term ``disability'' should be defined 
and is proposing a definition in the notice of proposed rulemaking 
found elsewhere in this issue of the Federal Register.
4. Increased Frequency
    Four comments on proposed Sec. 600.80(a) requested clarification of 
the definition for ``increased frequency.'' Two comments stated that 
the proposed definition of ``increased frequency,'' as an increase in 
the rate of occurrence, is misleading inasmuch as the rate of 
occurrence cannot be determined by a spontaneous reporting system. Two 
comments requested that the definition of increased frequency take into 
account an adjustment for product exposure.
    The agency agrees with these comments and is revising the 
definition in Sec. 600.80(a) as follows: ``Increased frequency means an 
increase in the rate of occurrence of a particular adverse biological 
product experience, after appropriate adjustment for exposure to the 
biological product.''
5. Life Threatening
    One comment requested that a definition for ``life threatening'' be 
included, similar to that found in 21 CFR 312.32.
    The agency agrees and is proposing a definition of ``life 
threatening'' in the notice of proposed rulemaking found elsewhere in 
this issue of the Federal Register.
6. Serious
    Three comments noted discrepancies between the preamble, 
Sec. 600.80(a) of the proposed rule, reporting form FDA-1639, and the 
draft guideline regarding the meaning of the term ``serious.'' The 
discrepancies consisted of differences in scope regarding the 
reportability of overdose, prolonged hospitalization, and severe 
disability.
    To clarify the discrepancies concerning ``overdose,'' the agency 
reevaluated the definition of ``serious'' to determine whether all 
overdoses should be included in the definition and determined that not 
all overdoses are serious.
    In resolving the discrepancies in the definition of ``serious'' 
regarding inpatient hospitalization, the agency determined that 
prolonged inpatient hospitalization should be included as a serious 
adverse event. FDA is proposing a revision of the definition of 
``serious'' to exclude the term ``overdose'' and to include ``requires 
or prolongs inpatient hospitalization'' in the notice of proposed 
rulemaking found elsewhere in this issue of the Federal Register.
    The term ``disability'' is discussed in section III.B.3 of this 
preamble.
7. Significant
    One comment requested that a definition for the word 
``significant'' which compensates for changes in use patterns be 
included in Sec. 600.80(a). The comment is in reference to the use of 
the term ``significant'' in the increased frequency alert reports.
    The agency agrees in part with this comment. The agency considers 
``significant'' in this context to mean a noticeable or measurable 
increase in frequency after adjustment for documented changes in use 
patterns. However, the agency is not codifying this definition in 
Sec. 600.80(a) because ``significant'' may have a different meaning in 
a different context within adverse experience reporting. The guideline 
provides clarifying examples utilizing a formula and table to determine 
if there is a significant increase in frequency of an adverse 
experience.
8. Clarification Between Product Defects and Adverse Experiences
    One comment requested clarification regarding the definitions in 
Sec. 600.80(a) for adverse experiences and the reporting of product 
defects.
    The definition of ``adverse experience'' in Sec. 600.80(a) 
specifies that the adverse experience must be ``associated with the use 
of a biological product in humans * * *.'' Therefore, product defects 
either discovered in the manufacturing process or not associated with 
an adverse experience in humans are not subject to this regulation. 
These defects may be reportable under good manufacturing practice 
regulations covered in 21 CFR 600.14. However, product defects which 
result in an adverse experience in a human are subject to reporting 
under Sec. 600.80.

C. Review of Adverse Experiences Section 600.8(b)

1. Reported by Scientific Papers or Competitors
    One comment on proposed Sec. 600.80(b) stated that to place 
responsibility on the licensed manufacturer for review of all adverse 
experience information pertaining to its product from any source, 
including published and unpublished scientific papers, is both time 
consuming and possibly open to abuse by competitors. The comment went 
on to state that if an unsubstantiated mailing from a competitor 
alleged ``adverse or unexpected experiences,'' the licensed 
manufacturer becomes subject to the entire 15-day alert procedures, 
including the need to conduct, if not actually report to FDA, the 
followup investigation. One comment asked the agency to specify the 
degree of vigor that licensed manufacturers should use to pursue 
reports of adverse experiences in the scientific literature.
    Section 600.80(b) is not intended to require licensed manufacturers 
to discover every published and unpublished report on its product. 
However, once a report of an adverse experience is made known to the 
licensed manufacturer, it is the licensed manufacturer's responsibility 
to comply with the requirements in Sec. 600.80 regardless of the source 
of the adverse experience report. It is acceptable for the licensed 
manufacturer to come to the conclusion that the mailing or publication 
alleging an adverse experience is false or misleading and report this 
conclusion to the agency. In some cases the agency may take appropriate 
regulatory action against persons preparing a false or misleading 
report of an adverse experience.
2. Lack of Response Reports
     One comment on proposed Sec. 600.80(b) stated that ``lack of 
response'' complaints from consumers do not have sufficient validity to 
aid in decisionmaking and therefore should not be submitted to FDA. 
Another comment requested that ``lack of response'' should not be 
submitted for single patient incidents but limited to studies.
    The agency believes that all reports of ``lack of response'' for 
single patient incidents should be reviewed and submitted by the 
licensed manufacturer. Complaints from consumers should be verified 
with the patient's health-care provider, if possible, prior to being 
submitted to FDA.

D. Clarification of Reporting Requirements Section 600.80(c)

1. Terminology
    Two comments on proposed Sec. 600.80(c) requested clarification of 
terminology between the term ``applicant'' used in Sec. 314.80 and the 
term ``manufacturer'' used in proposed Sec. 600.80. One comment 
preferred the term ``licensee'' for this regulation regarding 
biological products.
    The agency uses the term ``licensed manufacturer'' in these rules 
because it presents a more accurate representation of those required to 
comply with these regulations. These rules are being promulgated for 
the purpose of gathering postmarketing surveillance information, which 
will occur after product licensing.
2. Responsibilities
    Two comments requested clarification of responsibilities for joint 
manufacturers, shared manufacturers, divided manufacturers, and 
contractual manufacturers so that duplicate adverse experience reports 
are not submitted. One comment requested that, in order to avoid 
duplicate reporting or failures to report adverse experiences, the 
agency should add language similar to Sec. 314.80(c)(1)(iii). Another 
comment requested that the agency specify the reporting requirements of 
a nonapplicant.
    FDA recognizes that manufacturing of a biological product can be 
shared or divided among a number of business establishments. In the 
Federal Register of November 25, 1992 (57 FR 55544), FDA published a 
notice that discussed cooperative manufacturing arrangements for 
licensed biological products. In addition, 21 CFR 600.12(e) requires 
that ``each participating manufacturer shall furnish to the 
manufacturer who prepares the product in final form for sale, barter or 
exchange, a copy of all records relating to the manufacturing 
operations performed by such participating manufacturer insofar as they 
concern the safety, purity and potency of the lots of the product 
involved, * * *.'' Other requirements regarding divided manufacturing 
are contained in 21 CFR 610.63, which requires that ``If two or more 
establishments participate in the manufacture of a product, the name, 
address, and license number of each must appear on the package label, 
and on the label of the container if capable of bearing a full label.''
    The agency is clarifying the reporting requirements in 
Sec. 600.80(c)(1)(iii) by substituting the term ``licensed 
manufacturer'' for the term ``manufacturer.'' The agency intends that 
the manufacturer licensed to prepare the final product for commercial 
distribution has the primary responsibility for reporting adverse 
experiences to FDA. To prevent duplicate reports, language has been 
added to Sec. 600.80(c)(1)(iii) in this final rule to clearly delineate 
the responsibilities of the licensed manufacturer of the final product 
and other persons whose names may appear on the product label.

E. Reporting Requirements Section 600.80(c)

1. Failure of Pharmacologic Action
    One comment on proposed Sec. 600.80(c) requested that FDA not 
require single patient adverse experience forms for each failure of 
expected pharmacological action. The comment suggested that increased 
frequency analyses should not be performed on spontaneous lack of 
response reports because it is not possible for an appropriate baseline 
to be constructed using either domestic or foreign spontaneous reports 
in this setting.
    FDA believes that the use of single patient adverse experience 
reporting forms provides the agency with information that may be 
helpful in assessing whether there is a need for further investigation 
of the reported lack of response. The agency also believes that 
increased frequency analyses and reports are useful to serve as an 
indicator that an investigation is needed to explore the issue further.
2. Followup Reports to 15-day Alerts
    Two comments regarding proposed Sec. 600.80(c)(1)(i) questioned the 
need for a report that briefly describes the steps taken to seek 
additional information about an adverse event and the reasons why such 
information could not be obtained. The comments stated that the 
proposed language placed an additional burden on licensed manufacturers 
by requesting not only that they make every effort to obtain such 
information but also that they write a report describing such efforts.
    Under Sec. 600.80(c) licensed manufacturers will be required to 
seek additional information and document the steps taken to comply with 
the rule in a manner consistent with Sec. 314.80(c). The agency is not, 
at this time, specifying the format for this documentation. The agency 
must be able to verify the licensed manufacturer's efforts and advise 
licensed manufacturers of additional steps that should be pursued to 
retrieve the necessary information when appropriate. The proposed rule 
stated that this report should not be submitted to the agency unless so 
requested but should be maintained in the licensed manufacturer's 
files. This requirement differs from Sec. 314.80(c)(1)(i). The agency 
believes it would reduce the burden for manufacturers who produce both 
biologics and drugs if Sec. 600.80(c)(1)(i) is consistent with 
Sec. 314.80(c)(1)(i). Therefore, the sentence in proposed 
Sec. 600.80(c)(1)(i), ``This report should be retained by the 
manufacturer in its files but not submitted as a followup to FDA unless 
so requested'' has been deleted. Further discussion of changing the 
final disposition of these reports is included in the notice of 
proposed rulemaking found elsewhere in this issue of the Federal 
Register.
3. Increased Frequency Analysis
    Two comments on proposed Sec. 600.80(c)(1)(ii) requested 
information regarding the utility of increased frequency analysis. 
These comments suggest that the analysis is not of the increased 
frequency of adverse experiences but rather the analysis is of the 
increased frequency of reports of adverse experiences. One comment 
requested that the agency develop improved methods for determining 
increased frequency that would account for fluctuations in reporting.
    FDA agrees that increased frequency of adverse experience reports 
does not necessarily correlate with an increase in adverse experiences. 
Case reports are used to alert the agency about areas which may need 
further investigation. FDA takes into account the fact that reporting 
rates vary over time in postmarketing surveillance when analyzing the 
reporting rate for an individual biologic. FDA does not assume that an 
increase in incidence of adverse experiences will automatically trigger 
an increase in reports of adverse experience. Nor does the agency 
assume that an increase in the number of reports of adverse experiences 
necessarily indicates an increase in incidence of adverse experiences. 
The agency believes that an increase in reporting rates, when taken 
into account with other relevant information, may indicate that an 
epidemiologic investigation is needed to explore the situation further.
4. Periodic Reports
    Three comments on proposed Sec. 600.80(c)(2) noted a discrepancy on 
when the reporting period begins. One comment requested that the 
interval for periodic reporting be extended to annually rather than 
quarterly. One comment requested that the agency extend the time for 
submitting periodic reports from 30 to 60 days after the end of the 
reporting period.
    FDA believes that the reports need to be submitted in a timely 
manner because the public is continuing to be exposed to the products. 
Accordingly, FDA is retaining the proposed time schedule for submitting 
periodic reports in this final rule. In the notice of proposed 
rulemaking published elsewhere in this issue of the Federal Register, 
FDA is proposing to amend the regulations regarding when the reporting 
period begins and to amend the schedule for submitting periodic 
reports.
5. Schedule for Submitting Reports
    Four comments on proposed Sec. 600.80(c)(2)(i) requested that the 
agency limit reporting requirements (other than 15-day alerts) to the 
first 3 or 10 years of marketing. These comments stated that the 
initial postmarketing period would provide the most benefit and that 
after an initial period these reports would offer little benefit and 
would be a burden to the agency and the licensed manufacturer.
    FDA believes that there is a need for licensed manufacturers to 
continually monitor adverse experiences. The length of time a product 
is marketed does not guarantee that it will not be implicated in latent 
adverse experiences that were not recognized previously. Novel adverse 
experiences can occur when a biological product is used concomitantly 
with another drug or biological product. In addition, a product that 
has been on the market for many years can be implicated in adverse 
experiences that were either previously undetected or unknown in the 
scientific community. For these reasons, this requirement for periodic 
review and submission of reports of adverse experiences is necessary 
for the public safety. However, the licensed manufacturer can request a 
waiver under Sec. 600.90 in order to decrease or eliminate the periodic 
reporting requirements for older products with a proven safety record.
    Under Sec. 600.80(c)(2)(i) the agency may also require more 
frequent reports for products if appropriate; for example, products 
with special safety or efficacy concerns. Similarly the agency may 
require less frequent reports or no reports for products with a history 
of continual safety.
6. Effect of Significant Change in Manufacturing on Reporting 
Requirements
    One comment on proposed Sec. 600.80(c)(2)(i) expressed concern that 
significant changes in the manufacturing process, as provided in the 
Product License Application (PLA), may lead FDA to require that the 
frequency of the periodic reports be maintained as quarterly reports. 
The example given in the comment was for influenza virus vaccine. The 
comments questioned whether this product would be considered a new 
product annually due to its inherent strain changes.
    Influenza vaccine is an example of a product for which more 
frequent reports may be appropriate. The agency considers the influenza 
vaccine to be a new product annually because variations in influenza 
strains make it necessary to reformulate the influenza vaccine each 
year.
    In the past, there have been many reports of adverse experiences 
associated with the influenza vaccine, including reports of Guillain-
Barre Syndrome and false positive test results for other viral markers. 
In situations such as this, the agency may require more frequent 
reporting which will help it assess the magnitude and accuracy of 
reports of adverse experiences. In Sec. 600.80(c)(2)(i) FDA may upon 
written notice extend or reestablish the requirement that a licensed 
manufacturer submit quarterly reports, or require that the license 
manufacturer submit reports under this section at different times than 
those stated. Prompt reporting of these adverse experiences will make 
it easier to either recall a problem lot or discredit a false rumor.
7. Requirement for Negative Periodic Reports
    Two comments on proposed Sec. 600.80(c)(2) requested that the 
agency clarify the discrepancy between the proposed rule and the draft 
guideline regarding periodic reports for products that had no adverse 
experiences reported. The proposed rule did not require periodic 
reports for products that had no adverse experiences reported. The 
guideline asked that a letter be sent stating that no adverse 
experiences were reported. These comments also stated that the negative 
report is an ``undue burden.''
    The guideline has been changed to be consistent with the final rule 
in not requiring negative reporting at this time. However, the agency 
believes that the negative reports are appropriate for the agency to 
determine that the licensed manufacturer is focusing attention on 
whether there have been adverse experiences reported to FDA. Therefore, 
requirements regarding submission of negative reports are included in 
the notice of proposed rulemaking found elsewhere in this issue of the 
Federal Register.
8. Tabular Line Listing in Periodic Reports
    Three comments on proposed Sec. 600.80(c)(2)(ii)(C) regarding the 
tabular listing of adverse experiences required in the periodic reports 
stated that the requirements to list the patient's identification 
number, age, sex, and adverse experience terms in the tabular listing 
were viewed as unnecessary and excessive. Also noted were discrepancies 
regarding the tabular listing requirements between the guideline and 
the proposed rule.
    The agency agrees that the age and sex are not necessary in the 
tabular listing. However, the agency believes that the adverse 
experience terms should be included in such a listing. The tabular line 
listing is intended to provide a synopsis of individual case histories 
previously submitted, to assist FDA in identifying potential issues and 
individual case histories for further review. The agency is amending 
Sec. 600.80(c)(2) to require only the licensed manufacturer's patient 
identification number and adverse experience terms in the tabular 
listing.
9. Submission of Labeling
    Two comments on proposed Sec. 600.80(c)(2)(ii)(E) requested that 
the agency not require licensed manufacturers to submit with periodic 
reports a copy of the most current labeling, including container 
labels, carton labels, package inserts, and other materials distributed 
with the product. In addition, the comments stated that the current 
labeling is reviewed by FDA before use and licensed manufacturers 
should not be required to repeatedly submit this information with 
periodic reports. One comment stated that the only labeling useful for 
evaluating adverse experience reports is the package insert, unless the 
product is sold over-the-counter, then submission of directions for 
consumers on the container label may be justified.
    The agency agrees with the comments and is amending 
Sec. 600.80(c)(2)(ii)(C) of the final rule to require ``a history of 
actions taken since the last report because of adverse experiences (for 
example, labeling changes or studies initiated).'' This ensures that 
the review of the adverse experiences is conducted in the context of 
the latest information available.
10. Submission of Distribution Data
    Ten comments related to various aspects of the requirements in 
proposed Sec. 600.80(c)(2)(iv) for submission of distribution data for 
licensed biological products. Two comments stated that the request for 
foreign distribution data is a heavy burden. Three comments stated that 
the requirement to report dose distribution data is difficult and 
inappropriate for certain types of products and that this information 
is not required in Sec. 314.80 for drugs. Two comments disagreed with a 
statement in the preamble that the quantity of a product distributed 
enables FDA to estimate more accurately the incidence of a product's 
adverse effects. The comments reasoned that distribution data do not 
determine how much product is actually used. One comment questioned 
FDA's ability to keep the distribution information confidential. One 
comment stated that the proposed schedule for distribution reports 
places a hardship on manufacturers as it required quarterly reports for 
new biological products, annual reports for biological products 
licensed more than 3 years, and annual reports for drugs. Another 
comment requested guidance on the preferred format for distribution 
data. The agency agrees that foreign distribution data should not be 
required for biological products. Although the agency agrees that 
distribution data do not accurately estimate the incidence of a 
product's adverse effects, it is information needed to help FDA 
determine whether further study is needed. FDA, on its own initiative, 
is amending the final rule to parallel the drug regulations format by 
moving the requirements to submit distribution data to Sec. 600.81. The 
agency has revised the schedule for submitting distribution reports in 
Sec. 600.81 of the final rule. The reports will now be due on the 
semiannual and annual anniversary of the licensing of the product. 
Licensed manufacturers that believe that the requirements for 
submission of distribution data are inappropriate for certain types of 
products may request a waiver under Sec. 600.90, as discussed elsewhere 
in this preamble. Until a waiver is granted the provisions specified in 
the final rule are applicable.

F. Review of Scientific Literature

    One comment on Sec. 600.80(d) requested that submission of reports 
from scientific literature be limited to those articles where the 
author believes the product is associated with the experience; i.e., 
``reasonable causation'' by the author should be used in determining 
what adverse experiences from the literature need to be reported to 
FDA.
    The agency believes that reports of adverse experiences in the 
literature where the author clearly states that the licensed 
manufacturer's product is not the cause do not need to be reported. 
Reports in the scientific literature where no conclusion is reached 
regarding causality should be further investigated by the licensed 
manufacturer and reported to FDA if the adverse experience is 
associated or remains possibly associated with the licensed biological 
product. The licensed manufacturer should document the information that 
determines the cause to be other than product related and retain this 
documentation.

G. Reporting Form FDA-1639

    Five comments on proposed Sec. 600.80(f) concerned the use of Form 
FDA-1639 for reporting adverse experiences. One comment stated that the 
form is inappropriate for their biological products, one comment asked 
that the form be updated, one comment requested that Form FDA-1639 be 
retained for VAERS reporting as well as for adverse experience 
reporting for drugs and biological products. Two comments questioned 
whether an approved alternate form for reporting adverse experiences 
for drugs must be resubmitted to CBER for approval. One comment 
requested that the agency not allow implementation of an alternative 
reporting form as it will cause a hardship in computerization of 
adverse experience data across the biological and pharmaceutical 
product lines. This comment requested that the same form (Form FDA-
1639) be used for all adverse experience reports regardless of the 
nature of the product.
    FDA has designed a new adverse experience reporting form (Form FDA-
3500A) which, with the exception of reporting adverse experiences 
associated with vaccines, is ordinarily to be used to report under 
Secs. 310.305, 312.32, 314.80, 600.80, and parts 803 and 807 regarding 
drugs, biological products, and devices, respectively. The new form 
will simplify and consolidate the reporting of adverse events and 
product problems and will enhance agency-wide consistency in the 
collection of postmarketing data. Any computer-generated forms will 
have to be submitted to MEDWATCH, 5600 Fishers Lane, Rockville, MD 
20852-9787, for approval to use in complying with this final rule. As 
one comment suggested, alternative formats will make computerization of 
adverse experience data across product lines difficult. Therefore, a 
licensed manufacturer should submit adequate justification for an 
alternative format.
    Form FDA-3500A is referenced in Sec. 600.80(f) of the final rule. 
The term ``form designated by FDA'' is used throughout the remainder of 
the final rule to accommodate any future changes in the form itself. 
For vaccines the designated form for reporting adverse experiences is 
Form VAERS-1. The form for VAERS is discussed in a published report in 
Morbidity and Mortality Weekly Report (see MMWR, 39:730-733, 1990).

H. Reporter Identification

    One comment on proposed Sec. 600.80(h) requested that if the 
reporter is the patient (or relative) that his or her name not be 
listed on the adverse experience form.
    The agency concurs with this request for adverse experience 
reporting for licensed biological products other than vaccine-
associated experiences being reported in accordance with NCVIA. Under 
NCVIA it would be appropriate to include the patient's name in the 
report because copies of this report may be made available to the 
vaccinee or legal representative of the vaccinee. For adverse 
experience reporting of licensed biological products other than 
vaccines being reported under NCVIA, the report should not include the 
name of the patient, but should assign a unique code number to each 
report. For adverse experience reporting of biological products, 
patient identifiers are not releasable to the public under FDA's public 
information regulations (21 CFR part 20). Section 600.80(h) is amended 
to reflect that VAERS reports are subject to the CDC Privacy Act 
System.

I. Unique Code Number

    One comment concerning proposed Sec. 600.80(h) requested that the 
agency increase the number of characters in the unique code number 
assigned to each report from eight characters in length to nine 
characters.
    The agency encourages consistency by designating in the final rule 
a number of characters to be used, to simplify preparing and processing 
the reports. To allow some flexibility, note that Sec. 600.80(h) in the 
final rule recommends but does not require use of a code number of 
eight characters or less.

J. Recordkeeping

    Two comments on proposed Sec. 600.80(i) related to the length of 
time a licensed manufacturer is required to keep adverse experience 
records. One comment requested clarification regarding whether form 
letters sent by the licensed manufacturer to the adverse experience 
reporter must be retained 10 years; another comment requested that the 
recordkeeping be limited to 1 year past the involved product's 
expiration date.
    FDA believes that 10 years is a reasonable time to maintain such 
records. This requirement corresponds with existing regulations for 
drug products. If a form letter to the reporter is the documentation 
that the licensed manufacturer sought additional information about an 
adverse experience, then the form letter must be maintained in the file 
for 10 years. Any letters which are part of the correspondence 
regarding an adverse experience reporting must be maintained in the 
file for 10 years.

K. Exemptions

    FDA has determined that Sec. 600.80(l) should be amended to clarify 
that licensed manufacturers of in vitro diagnostic products, including 
assay systems for the detection of antibodies or antigens to 
retroviruses, report adverse experiences under the device reporting 
regulations. The best way to monitor product defects with these 
licensed biological devices is for them to be reported under the 
Medical Devices: Medical Device User Facility, Distributor, and 
Manufacturer Reporting, Certification, and Registration Regulations 
(see 56 FR 60024, November 26, 1991). To eliminate any confusion over 
how to report product defects with these products, the final rule is 
amended to state specifically that in vitro diagnostics, including 
assays to detect antibodies or antigens to retroviruses (such as HIV-1 
and HIV-2), are exempt from this rule but are subject to the device 
reporting regulations.

IV. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354). 
Executive Order 12866 directs agencies to assess all costs and benefits 
of available regulatory alternatives and, when regulation is necessary, 
to select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The agency believes that 
this final rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order. In addition, the final 
rule is not a significant regulatory action as defined by the Executive 
Order and so is not subject to review under the Executive Order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. The final rule codifies adverse experience reporting 
for biological products currently being practiced by licensed 
manufacturers on a voluntary basis. FDA believes that the information 
collection resulting from postmarket surveillance required by this 
final rule will be of benefit to the public health. FDA has prepared a 
Threshold Assessment to estimate the cost to comply with the final rule 
by the regulated industry. The estimation by FDA for the total annual 
cost to industry is $3,937,164. The agency certifies that the final 
rule will not have a significant economic impact on a substantial 
number of small entities. Therefore, under the Regulatory Flexibility 
Act, no further analysis is required.

V. Environmental Impact

    The agency has determined under 21 CFR 25.24(a)(8) that this action 
is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

VI. Paperwork Reduction Act of 1980

    Sections 600.80 and 600.81 of this final rule contain information 
collection requirements which are subject to review by the Office of 
Management and Budget (OMB) under the Paperwork Reduction Act of 1980. 
The title, description, and respondent description of the information 
collection are shown below with an estimate of the annual reporting and 
recordkeeping burden. Included in the estimate is the time for 
reviewing instructions, searching existing data sources, gathering and 
maintaining the data needed, and completing and reviewing the 
collection of information.
    Title: Adverse Experience Reporting Requirements for Licensed 
Biological Products.
    Description: FDA is charged with the responsibility for determining 
that a biological product meets the statutory standards for safety, 
purity, and potency for initial and continued licensure. To carry out 
this mandate, the agency needs to be informed whenever a manufacturer 
of a licensed biological product receives or otherwise becomes aware of 
information about adverse experiences associated with the use of its 
product. Only if FDA is provided with such information will it be able 
to evaluate the risk, if any, associated with a biological product and 
take whatever action is necessary to reduce or eliminate the public's 
exposure. FDA is taking this action to provide a mechanism under which 
manufacturers would inform the agency, on a timely basis, of any 
unanticipated safety problems with marketed biological products. This 
action is similar to initiatives taken by FDA regarding new drugs and 
medical devices.
    Description of Respondents: Businesses or other for-profit and 
small businesses or organizations.
    As required by the Paperwork Reduction Act, FDA has submitted a 
copy of this rule to OMB with a request that it approve these 
information collection requirements. 

                                                        Estimated Total Annual Reporting Burden                                                         
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                          Number of Respondents                                                                         
          Section              Number of Respondents         per Respondent        Total Annual Responses      Hours Per Response         Total Hours   
--------------------------------------------------------------------------------------------------------------------------------------------------------
600.81                                             63                 175.12698                    11,033                       1.0             11,033  
--------------------------------------------------------------------------------------------------------------------------------------------------------


                                  Estimated Total Annual Recordkeeping Burden                                   
----------------------------------------------------------------------------------------------------------------
                                                                                           Total Recordkeeping  
        Section            No. of Recordkeepers       Annual Hours Per Recordkeeper              Hours          
----------------------------------------------------------------------------------------------------------------
600.80(i)                                     63                                  0.5                      31.5 
----------------------------------------------------------------------------------------------------------------

    This final rule also contains information collection requirements 
contained in Sec. 600.80(c) that have been approved by OMB under OMB 
No. 0910-0291 with a total of 11,033 hours. It is estimated that the 
information requirements for this section under this final rule will 
add 11,064.5 hours to the burden estimate.

List of Subjects in 21 CFR Part 600

    Biologics, Reporting and recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act, the 
Public Health Service Act, and under authority delegated to the 
Commissioner of Food and Drugs, 21 CFR part 600 is amended as follows:

PART 600--BIOLOGICAL PRODUCTS: GENERAL

    1. The authority citation for 21 CFR part 600 is revised to read as 
follows:

    Authority: Secs. 201, 501, 502, 503, 505, 510, 519, 701, 704 of 
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 
353, 355, 360, 360i, 371, 374); secs. 215, 351, 352, 353, 361, 2125 
of the Public Health Service Act (42 U.S.C. 216, 262, 263, 263a, 
264, 300aa-25).

    2. A new subpart D consisting of Secs. 600.80, 600.81, and 600.90 
is added to read as follows:

Subpart D--Reporting of Adverse Experiences

Sec.
600.80   Postmarketing reporting of adverse experiences.
600.81   Distribution reports.
600.90   Waivers.

Subpart D--Reporting of Adverse Experiences


Sec. 600.80  Postmarketing reporting of adverse experiences.

    (a)  Definitions. The following definitions of terms apply to this 
section:
    Adverse experience means 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 for this purpose has the same meaning as defined in 
Sec. 606.3(c) of this chapter.
    Increased frequency means an increase in the rate of occurrence of 
a particular adverse biological product experience, e.g., an increased 
number of reports of a particular adverse biological product experience 
after appropriate adjustment for biological product exposure.
    Serious means an adverse experience associated with the use of a 
biological product that is fatal or life-threatening, is permanently 
disabling, requires inpatient hospitalization, or is a congenital 
anomaly, cancer, or overdose.
    Unexpected means an adverse biological product experience that is 
not listed in the current labeling for the product and includes an 
event that may be symptomatically and pathophysiologically related to 
an event listed in the labeling, but differs 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.
    (b) Review of adverse experiences. Any person having a product 
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.
    (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)  Fifteen-day Alert reports. (i) The licensed manufacturer shall 
report each adverse experience that is both serious and unexpected, 
regardless of source, as soon as possible but in any case within 15 
working days of initial receipt of the information. These reports are 
required to be submitted, for nonvaccine biological products, on a form 
designated by FDA or a suitable format containing all of the data 
elements in the FDA designated reporting form, and, for vaccines on a 
VAERS form. The licensed manufacturer shall promptly investigate all 
adverse experiences that are the subject of these 15-day Alert reports 
and shall submit followup reports within 15 working days of receipt of 
new information or as requested by FDA. If additional information is 
not obtainable, a followup report may be required that describes 
briefly the steps taken to seek additional information and the reasons 
why it could not be obtained. These 15-day Alert reports and followups 
to them are required to be submitted under separate cover and may not 
be included, except for summary or tabular purposes, in a periodic 
report.
    (ii) The licensed manufacturer shall review periodically (at least 
as often as the periodic reporting cycle) the frequency of reports of 
adverse biological product experiences that are both serious and 
expected and reports of therapeutic failure (lack of effect), 
regardless of source, and report any significant increase in frequency 
as soon as possible but in any case within 15 working days of 
determining that a significant increase in frequency exists. Upon 
written notice, FDA may require that licensed manufacturers review the 
frequency of reports of serious, expected adverse biological product 
experiences at intervals different than the periodic reporting cycle. 
Reports of a significant increase in frequency are required to be 
submitted in narrative form (including the time period on which the 
increased frequency is based, the method of analysis, and the 
interpretation of the results), rather than using the form designated 
by FDA. Fifteen-day Alert reports based on increased frequency are 
required to be submitted under separate cover and may not be included, 
except for summary purposes, in a periodic report.
    (iii) The requirements of paragraphs (c)(1)(i) and (c)(1)(ii) of 
this section, concerning the submission of Fifteen-day Alert reports, 
shall also apply to any person other than the licensed manufacturer of 
the final product 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. In order to avoid unnecessary duplication in the 
initial and followup submission of reports to FDA, the obligations of a 
manufacturer other than the licensed manufacturer, may be met by 
submitting all reports to the licensed manufacturer of the final 
product. If a manufacturer other than the licensed manufacturer elects 
to submit reports to the licensed manufacturer rather than to FDA, it 
shall submit each report to the licensed manufacturer within 3 working 
days of its receipt, and the licensed manufacturer shall then comply 
with the requirements of this section. Under this circumstance, the 
manufacturer 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,
    (B) Date the report was received by the manufacturer,
    (C) Date the report was submitted to the licensed manufacturer,
    (D) Name and address of the licensed manufacturer.
    (iv) 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 product 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 product license) and each annual report 
within 60 days of the anniversary date of the issuance of the product 
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. The 15-day Alert reporting requirements in paragraph 
(c)(1)(ii) of this section (i.e., a significant increase in frequency 
of a serious, expected adverse experience or of a therapeutic failure) 
apply only to reports found in scientific and medical journals either 
as the result of a formal clinical trial, or from epidemiologic studies 
or analyses of experience in a monitored series of patients.
    (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 paragraphs 
(c)(1)(ii), and (f)(3) of this section, the licensed manufacturer shall 
complete the reporting form designated by FDA (FDA-3500A, or, for 
vaccines, a VAERS form) for each report of an adverse experience.
    (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 experiences that occurred in 
clinical trials if they were previously submitted in the product 
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 license 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)  Guideline. FDA has prepared a guideline for the submission of 
reports of adverse experiences and suggested followup investigation of 
reports.
    (k)  Revocation of 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 product license for such a product in accordance with the 
procedures of Sec. 601.5 of this chapter.
    (l)  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.
    (m)  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.


Sec. 600.81 Distribution reports.

    The licensed manufacturer shall submit information about the 
quantity of the product distributed under the product license, 
including the quantity distributed to distributors. The interval 
between distribution reports shall be 6 months. Upon written notice, 
FDA may require that the licensed manufacturer submit distribution 
reports under this section at times other than every 6 months. The 
distribution report shall consist of the bulk lot number (from which 
the final container was filled), the fill lot numbers for the total 
number of dosage units of each strength or potency distributed (e.g., 
fifty thousand per 10-milliliter vials), the label lot number (if 
different from fill lot number), labeled date of expiration, number of 
doses in fill lot/label lot, date of release of fill lot/label lot for 
distribution at that time. If any significant amount of a fill lot/
label lot is returned, include this information. Disclosure of 
financial or pricing data is not required. As needed, FDA may require 
submission of more detailed product distribution information. Upon 
written notice, FDA may require that the licensed manufacturer submit 
reports under this section at times other than those stated. Requests 
by a licensed manufacturer to submit reports at times other than those 
stated should be made as a request for a waiver under Sec. 600.90.


Sec. 600.90   Waivers.

    (a) A licensed manufacturer may ask the Food and Drug 
Administration to waive under this section any requirement that applies 
to the licensed manufacturer under Secs. 600.80 and 600.81. A waiver 
request under this section is required to be submitted with supporting 
documentation. The waiver request is required to contain one of the 
following:
    (1) An explanation why the licensed manufacturer's compliance with 
the requirement is unnecessary or cannot be achieved,
    (2) A description of an alternative submission that satisfies the 
purpose of the requirement, or
    (3) Other information justifying a waiver.
    (b) FDA may grant a waiver if it finds one of the following:
    (1) The licensed manufacturer's compliance with the requirement is 
unnecessary or cannot be achieved,
    (2) The licensed manufacturer's alternative submission satisfies 
the requirement, or
    (3) The licensed manufacturer's submission otherwise justifies a 
waiver.

    Dated: October 13, 1994.
William K. Hubbard,
Interim Deputy Commissioner for Policy.
[FR Doc. 94-26482 Filed 10-26-94; 8:45 am]
BILLING CODE 4160-01-F