Adverse Experience Reporting Requirements for Licensed Biological Products

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