Federal Register / Vol. 62, No. 194 / Tuesday, October 7, 1997 / Rules and Regulations 52237

(b) For purpose of this section, lost

securityholder means a securityholder:

(1) To whom an item of

correspondence that was sent to the

securityholder at the address contained

in the transfer agent’s master

securityholder file has been returned as

undeliverable; provided, however, that

if such item is re-sent within one month

to the lost securityholder, the transfer

agent may deem the securityholder to be

a lost securityholder as of the day the resent item is returned as undeliverable

and

(2) For whom the transfer agent has

not received information regarding the

securityholder’s new address.

3. Section 240.17Ad–7 is amended by

adding paragraph (i) to read as follows:

§ 240.17Ad–7 Record retention.

* * * * *

(i) The records required by

§ 240.17Ad–17(c) shall be maintained

for a period of not less than three years,

the first year in an easily accessible

place.

4. Section 240.17Ad–17 is added to

read as follows:

§ 240.17Ad–17 Transfer agents’ obligation

to search for lost securityholders.

(a)(1) Every recordkeeping transfer

agent whose master securityholder file

includes accounts of lost

securityholders shall exercise

reasonable care to ascertain the correct

addresses of such securityholders. In

exercising reasonable care to ascertain

for its master securityholder file such

lost securityholders’ current addresses,

each recordkeeping transfer agent shall

conduct two data base searches using at

least one information data base service.

The transfer agent shall search by

taxpayer identification number or by

name if a search based on taxpayer

identification number is not reasonably

likely to locate the securityholder. Such

data base searches must be conducted

without charge to a lost securityholder

and with the following frequency:

(i) Between three and twelve months

of such securityholder becoming a lost

securityholder and

(ii) Between six and twelve months

after the transfer agent’s first search for

such lost securityholder.

(2) A transfer agent may not use a

search method or service to establish

contact with lost securityholders that

results in a charge to a lost

securityholder prior to completing the

searches set forth in paragraph (a)(1) of

this section.

(3) A transfer agent need not conduct

the searches set forth in paragraph (a)(1)

of this section for a lost securityholder

if:

(i) It has received documentation that

such securityholder is decreased or

(ii) The aggregate value of assets listed

in the lost securityholder and all

securities owned by the lost

securityholder as recorded in the

transfer agent’s master securityholder

files, is less than $25; or

(iii) The securityholder is not a

natural person.

(b) For purposes of this section:

(1) Information data base service

means either:

(i) Any automated data base service

that contains addresses from the entire

United States geographic area, contains

the names of at least 50% of the United

States geographic area, contains the

names of at least 50% of the United

States adult population, is indexed by

taxpayer identification number or name,

and is updated at least four times a year;

or

(ii) Any service or combination of

services which produces results

comparable to those of the service

described in paragraph (b)(1)(i) of this

section in locating lost securityholders.

(2) Lost securityholder means a

securityholder:

(i) To whom an item of

correspondence that was sent to the

securityholder at the address contained

in the transfer agent’s master

securityholder file has been returned as

undeliverable; provided, however, that

if such item is re-sent within one month

to the lost securityholder, the transfer

agent may deem the securityholder to be

a lost securityholder as of the day the

resent item is returned as undeliverable;

and

(ii) For whom the transfer agent has

not received information regarding the

securityholder’s new address.

(c) Every recordkeeping transfer agent

shall maintain records to demonstrate

compliance with the requirements set

forth in this section which shall include

written procedures which describe the

transfer agent’s methodology for

complying with this section.

PART 249b—FURTHER FORMS,

SECURITIES EXCHANGE ACT OF 1934

5. The authority citation for part 249b

continues to read in part as follows:

Authority: 15 U.S.C. 78a, et seq., unless

otherwise noted;

* * * * *

Note: Form TA–2 does not and the

amendments will not appear in the Code of

Federal Regulations.

§ 249b.102 [Form TA–2 Amended]

6. Form TA–2 (referenced in

§ 249b.102) is amended by adding

paragraph 8 to Instruction I.A. to read as

follows:

Form TA–2

* * * * *

I. General Instruction for Filing and

Amending Form TA–2.

A. * * *

8. ‘‘Lost securityholder’’ is defined in

Rule 17a–24(b)(1) (17 CFR 240.17a–

24(b)(1)).

* * * * *

§ 249b.102 [Form TA–2 Amended]

7. Form TA–2 (referenced in

§ 249b.102) is amended by adding

paragraph c to Question 4 to read as

follows:

Form TA–2

* * * * *

4. * * *

c. (i) Number of lost securityholder

accounts and (ii) percentage of total

accounts represented by lost

securityholder accounts as of June 30

for:

Accounts of securityholders lost one year or

less: llllllllllllllllll

Accounts of securityholders lost three years

or less: lllllllllllllllll

Accounts of securityholders lost five years or

less: llllllllllllllllll

Accounts of securityholders lost more than

five years: llllllllllllllll

Accounts of securityholders which have

escheated to states within the year ended

June 30: lllllllllllllllll

* * * * *

Dated: October 1, 1997.

By the Commission.

Margaret H. McFarland,

Deputy Secretary.

[FR Doc. 97–26519 Filed 10–6–97; 8:45 am]

BILLING CODE 8010–01–M

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 20, 310, 312, 314, and 600

[Docket No. 93N–0181]

RIN 0910–AA97

Expedited Safety Reporting

Requirements for Human Drug and

Biological Products

AGENCY: Food and Drug Administration,

HHS.

ACTION: Final rule.

SUMMARY: The Food and Drug

Administration (FDA) is amending its

expedited safety reporting regulations

for human drug and biological products

to provide consistency with the

elements of FDA Form 3500A for use in

pre- and postmarketing safety reporting;
52238 Federal Register / Vol. 62, No. 194 / Tuesday, October 7, 1997 / Rules and Regulations

implement definitions, reporting

periods, formats, and standards as

recommended by the International

Conference on Harmonisation of

Technical Requirements for Registration

of Pharmaceuticals for Human Use (ICH)

and by the World Health Organization’s

Council for International Organizations

of Medical Sciences (CIOMS); require

applicants, manufacturers, packers, and

distributors, as well as licensed

manufacturers and other manufacturers

of biological products, to develop

written procedures for postmarketing

safety monitoring and reporting; state

that FDA Form 3500A reports that FDA

forwards to any person subject to the

postmarketing safety reporting

requirements are not required to be

resubmitted to the agency; and make

other revisions to the regulations to

provide uniformity with definitions and

procedures used in expedited pre- and

postmarketing safety reporting for

human drug and biological products.

These changes simplify and facilitate

expedited safety reporting and enhance

agencywide consistency in the

collection of postmarketing safety data.

DATES: This regulation is effective April

6, 1998. Submit written comments on

the information collection provisions of

this final rule by December 8, 1997.

ADDRESSES: Submit written comments

on the information collection provisions

of this final rule to the Dockets

Management Branch (HFA–305), Food

and Drug Administration, 12420

Parklawn Dr., rm. 1–23, Rockville, MD

20857.

FOR FURTHER INFORMATION CONTACT:

For information concerning human

drug products: Audrey A. Thomas,

Center for Drug Evaluation and

Research (HFD–7), Food and Drug

Administration, 5600 Fishers Lane,

Rockville, MD 20857, 301–594–

5625.

For information concerning human

biological products: Valerie A.

Butler, Center for Biologics

Evaluation and Research (HFM–17),

Food and Drug Administration,

1401 Rockville Pike, suite 200N,

Rockville, MD 20852–1448, 301–

594–3074.

SUPPLEMENTARY INFORMATION:

I. Introduction

In the Federal Register of October 27,

1994 (59 FR 54046), FDA published a

proposed rule to amend the regulations

for expedited and periodic pre- and

postmarketing safety reporting for

human drug and biological products

(hereinafter referred to as the October

1994 proposal). FDA also proposed to

amend the requirements for clinical

study design and conduct and annual

sponsor reporting in the investigational

new drug application (IND) regulations.

As explained in the October 1994

proposal, the amendments to the safety

reporting regulations are intended to

provide consistency with certain

standardized definitions, procedures,

and formats developed by ICH and

CIOMS (59 FR 54046 at 54047). In the

Federal Register of July 9, 1993 (58 FR

37408), FDA published an ICH draft

guideline entitled ‘‘Clinical Safety Data

Management: Definitions and Standards

for Expedited Reporting’’ (hereinafter

referred to as the draft ICH E2A

guideline). The public was given an

opportunity to comment on the draft

ICH E2A guideline. After consideration

of the comments received and revisions

to the draft guideline, ICH finalized the

guideline. In the Federal Register of

March 1, 1995 (60 FR 11284), FDA

published the ICH final guideline

(hereinafter referred to as the final ICH

E2A guideline). Although the final ICH

E2A guideline pertains to expedited

safety reporting during the preapproval

phase of drug development, for

consistency and simplicity many of the

definitions, reporting periods, formats,

and standards also could apply to FDA’s

expedited postmarketing safety

reporting requirements.

In this final rule, FDA is amending its

regulations for expedited safety

reporting to implement certain

definitions, reporting periods, and

formats recommended in the final ICH

E2A guideline. FDA is considering other

recommendations in the final ICH E2A

guideline that were not included in the

October 1994 proposal and plans to

propose additional amendments to its

expedited safety reporting regulations

shortly (e.g., pre- and postmarketing

reporting of adverse drug reactions

rather than adverse drug experiences,

submission of expedited safety reports

to FDA from clinical investigations

based on the opinion of either the

sponsor or investigator).

FDA is delaying finalization of the

proposed amendments to the periodic

postmarketing safety reporting

regulations (59 FR 54046). The proposed

amendments were based, for the most

part, on recommendations developed by

the CIOMS Working Group II (Ref. 1).

ICH also developed recommendations,

based on the CIOMS Working Group II

proposals, for periodic postmarketing

safety reporting. In the Federal Register

of May 19, 1997 (62 FR 27470), FDA

published an ICH final guideline

entitled ‘‘Clinical Safety Data

Management: Periodic Safety Update

Reports for Marketed Drugs’’

(hereinafter referred to as the ICH E2C

guideline). FDA will finalize the

proposed amendments to the periodic

postmarketing safety reporting

regulations after consideration of the

provisions of the ICH E2C guideline.

In light of the comments the agency

received, FDA has reconsidered the

proposed amendments to the

requirements for clinical study design

and conduct and annual sponsor

reporting under the IND (59 FR 54046).

In general, the comments opposed the

proposed amendments because the

current IND regulations protect the

safety of the public in all but the most

unusual cases. Based on these general

comments and others specific to each of

the proposed amendments, the agency

has decided to withdraw the proposed

amendments to the IND requirements

for clinical study design and conduct

and annual sponsor reporting. The

agency will, instead, develop a guidance

document providing recommendations

on study design and monitoring of

investigational drugs used to treat

serious and potentially fatal illnesses,

with particular attention to detection of

adverse events that are similar to those

caused by the underlying disease. In

developing the draft guidance

document, FDA will consider comments

submitted in response to the proposed

amendments and will provide

opportunity for public input on the

document prior to its implementation.

Thus, in this final rule, FDA is

withdrawing the proposed amendments

to the IND regulations (part 312 (21 CFR

part 312)) at §§ 312.23, the second

sentence of 312.32(c)(1)(i), 312.33,

312.37, 312.42, 312.44, 312.56, and

312.64 (59 FR 54046 at 54057 to 54059).

In the Federal Register of June 25,

1997 (62 FR 34166), FDA published a

final rule to amend its regulations on

expedited reporting of postmarketing

adverse experiences to revoke the

requirement for increased frequency

reports as expedited reports for human

drug and licensed biological products.

Thus, in this final rule, FDA is

withdrawing the proposed amendments

to the increased frequency reporting

requirements published in the October

1994 proposal.

II. Background

In the Federal Register of June 3, 1993

(58 FR 31596), FDA announced the

availability of a new form for reporting

single cases of adverse events and

product problems with medications,

devices, and other FDA-regulated

medical products (hereinafter referred to

as the June 1993 notice). This form is

available in two versions: FDA Form

3500 is for use by health care

professionals and consumers for
Federal Register / Vol. 62, No. 194 / Tuesday, October 7, 1997 / Rules and Regulations 52239

voluntary reporting; FDA Form 3500A is

for use by any person subject to FDA’s

mandatory safety reporting regulations.

Adverse events associated with vaccines

continue to be reported to FDA and the

Centers for Disease Control and

Prevention using the Vaccine Adverse

Event Reporting System (VAERS) form.

Under the existing regulations,

manufacturers, packers, and

distributors; applicants of approved new

and abbreviated marketing applications

for drugs and antibiotics; and licensed

manufacturers and other manufacturers

of biological products must submit

expedited reports of postmarketing

adverse drug experiences under 21 CFR

310.305, 314.80, 314.98, and 600.80.

Sponsors of IND’s must also submit

expedited reports, under § 312.32, for

adverse experiences associated with the

use of an investigational human drug or

biological product. Currently, there is

no standard form for these IND

expedited safety reports.

FDA Forms 3500 and 3500A are part

of FDA’s Medical Products Reporting

Program (MedWatch) and are designed

to facilitate safety reporting for most

FDA-regulated human medical products

by the entire health care community,

including manufacturers, distributors,

user facilities, and health care

professionals. FDA issued the new

forms to simplify and consolidate safety

reporting for human drug products,

biologics, and medical devices, as well

as other FDA-regulated medical

products. The new forms eliminate

redundant or nonessential elements

from past reporting forms and clarify

those areas that have caused confusion.

In developing FDA Forms 3500 and

3500A, and in developing the revisions

to the expedited safety reporting

regulations that are the subject of this

final rule, the agency considered several

ICH and CIOMS recommendations.

These organizations were formed to

facilitate international consideration of

issues, particularly safety issues,

concerning the use of both foreign and

domestic data in the development and

use of drugs and biological products.

ICH has worked to promote the

harmonization of technical

requirements for the registration of

pharmaceutical products among three

regions: The European Union, Japan,

and the United States. In addition,

several CIOMS working groups have

served to coordinate and standardize the

international reporting of suspected

postmarketing adverse drug reactions by

pharmaceutical manufacturers to

regulatory authorities. FDA believes the

changes recommended by CIOMS and

ICH will result in more effective and

efficient safety reporting to regulatory

authorities worldwide.

III. Description of the Final Rule

This final rule amends parts 20, 310,

312, 314, and 600 (21 CFR parts 20, 310,

312, 314, and 600) to revise definitions,

requirements, and procedures for

expedited pre- and postmarketing safety

reporting. This rulemaking finalizes

many of the expedited safety reporting

provisions as proposed in the October

1994 proposal. In addition, this final

rule reflects amendments to the October

1994 proposal that were made in

response to comments (discussed in

section IV of this document), including

comments recommending greater

consistency with the ICH E2A guideline

and uniformity between pre- and

postmarketing safety reporting

definitions. This final rule also

incorporates minor revisions for clarity

and further consistency. The major

provisions of the final rule are

summarized as follows:

1. FDA Forms 3500/3500A. As

proposed, the final rule permits

sponsors to submit IND safety reports,

under § 312.32(c)(1)(i), on FDA Form

3500A rather than in a narrative format,

and replaces, at §§ 310.305 and 314.80,

Form FDA–1639 with FDA Form 3500A

for use in postmarketing safety reporting

for human drug products. The final rule

also replaces, at § 20.112, Form FDA–

1639 with FDA Form 3500 for voluntary

drug experience reporting by physicians

and hospitals. The final rule, like the

proposed rule, instructs applicants,

manufacturers, packers, and distributors

to obtain approval from FDA’s

MedWatch office before using an

alternative reporting format for

postmarketing safety reporting under

§§ 310.305(d)(3)(ii) and 314.80(f)(3)(ii).

Pre- and postmarketing safety reporting

of foreign events may continue to be

reported to FDA on the CIOMS I form

(Ref. 2). After consideration of the

comments, the final rule, unlike the

proposed rule, permits use of the

CIOMS I form for this purpose without

prior FDA approval.

2. Definitions. In response to

comments, the proposed definition of

‘‘serious’’ at §§ 310.305(b), 312.32(a),

314.80(a), and 600.80(a) has been

revised to make it consistent with the

definition of ‘‘serious’’ in the final ICH

E2A guideline and with the definition of

‘‘serious’’ used in FDA Form 3500A. To

provide uniformity between the preand postmarketing definitions of

‘‘serious,’’ the following information has

been removed from the current

definition of ‘‘serious adverse

experience’’ at § 312.32(a) and added as

a reporting requirement to the IND

safety reporting regulations at

§ 312.32(c)(1)(i):

With respect to results obtained from tests

in laboratory animals, a serious adverse drug

experience includes any experience

suggesting a significant risk for human

subjects, including any finding of

mutagenicity, teratogenicity, or

carcinogenicity.

This revision represents an

organizational change that does not

impose a new burden because sponsors

are already required to report such

information to FDA.

In response to comments, the final

rule also amends the proposed

definitions of ‘‘disability’’ and ‘‘lifethreatening’’ at §§ 310.305(b), 314.80(a),

and 600.80(a) for consistency with the

final ICH E2A guideline and for clarity.

In addition, the definition of

‘‘disability’’ has been added to the

‘‘definitions’’ section of the

premarketing safety reporting

regulations at § 312.32(a), and the

definition of ‘‘life-threatening’’ has been

removed from the ‘‘telephone safety

report’’ section of the premarketing

safety reporting regulations at

§ 312.32(c)(2) and added to the

‘‘definitions’’ section of these

regulations at § 312.32(a). For further

clarity and consistency in reporting

adverse drug experiences that are lifethreatening, FDA has decided to

replace, at §§ 310.305(b), 312.32(a),

314.80(a), and 600.80(a), the word

‘‘serious’’ with ‘‘severe’’ so that the first

sentence of the definition of ‘‘lifethreatening’’ includes the following:

‘‘* * *, i.e., [Life-threatening] does not

include a reaction that, had it occurred

in a more severe form, might have

caused death.’’ As explained in the final

ICH E2A guideline, ‘‘severe’’ refers to

the intensity (severity) of a specific

event (e.g., mild, moderate, or severe

myocardial infarction); the event itself

may be of relatively minor medical

significance such as a severe headache.

The term ‘‘serious,’’ however, is based

on patient/event outcome or action

criteria usually associated with events

that pose a threat to a patient’s life or

functioning (e.g., an event that results in

death or that is life-threatening or

requires inpatient hospitalization) (60

FR 11284 at 11285). FDA has also

decided to remove the following

sentence from this definition: ‘‘For

example, drug-induced hepatitis that

resolved without evidence of hepatic

failure would not be considered lifethreatening even though drug-induced

hepatitis can be fatal.’’ Use of hepatitis

as an example for life-threatening may

be confusing because viral transmission

of certain types of hepatitis through

blood products could be life-
52240 Federal Register / Vol. 62, No. 194 / Tuesday, October 7, 1997 / Rules and Regulations

threatening. To harmonize pre- and

postmarketing safety reporting

definitions, FDA has decided to

withdraw the examples listed in the

proposed postmarketing definition of

‘‘life-threatening’’ at §§ 310.305(b),

314.80(a), and 600.80(a). The agency has

decided, instead, to revise the guidances

associated with this final rule to include

examples of life-threatening adverse

drug experiences (CDER’s ‘‘Guideline

for Postmarketing Reporting of Adverse

Drug Experiences,’’ March 1992 and

CBER’s ‘‘Guideline for Adverse

Experience Reporting for Licensed

Biological Products,’’ October 1993).

In this final rule, FDA is incorporating

minor changes to the definition of

‘‘unexpected’’ adverse drug experience

at §§ 310.305(b), 312.32(a), 314.80(a),

and 600.80(a) to provide uniformity

between pre- and postmarketing safety

reporting definitions and consistency

with the ICH E2A guideline.

The definition of ‘‘unexpected’’

adverse drug experience at

§§ 310.305(b), 314.80(a), and 600.80(a)

currently states:

* * * an adverse drug experience that is

not listed in the current labeling for the drug

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.

To clarify what must be reported to the

agency as an ‘‘unexpected adverse drug

experience,’’ FDA is amending this

definition by adding the following

sentence:

‘‘Unexpected,’’ as used in this definition,

refers to an adverse drug experience that has

not been previously observed (i.e., included

in the labeling) rather than from the

perspective of such experience not being

anticipated from the pharmacological

properties of the pharmaceutical product.

This amendment is consistent with the

discussion of ‘‘expectedness of an

adverse drug reaction’’ in the final ICH

E2A guideline:

The purpose of expedited reporting is to

make regulators, investigators, and other

appropriate people aware of new, important

information on serious reactions. Therefore,

such reporting will generally involve events

previously unobserved or undocumented,

and a guideline is needed on how to define

an event as ‘‘unexpected’’ or ‘‘expected’’

(expected/ unexpected from the perspective

of previously observed, not on the basis of

what might be anticipated from the

pharmacological properties of a medicinal

product).

The definition of ‘‘unexpected

adverse experience’’ at § 312.32(a)

currently states:

* * * any adverse experience that is not

identified in nature, severity, or frequency in

the current investigator brochure; or, if an

investigator brochure is not required, that is

not identified in nature, severity, or

freuquency [sic] in the risk information

described in the general investigational plan

or elsewhere in the current application, as

amended.

For clarity and consistency, FDA is

amending this definition to conform

with the definition of ‘‘unexpected’’ at

§§ 310.305(b), 314.80(a), and 600.80(a)

by removing the references to frequency,

replacing the word ‘‘nature’’ with the

word ‘‘specificity,’’ adding examples of

unexpected adverse drug experiences,

and making other minor revisions. The

revised definition at § 312.32(a) states:

Unexpected adverse drug experience: Any

adverse drug experience, the specificity or

severity of which is not consistent with the

current investigator brochure; or if an

investigator brochure is not required or

available, the specificity or severity of which

is not consistent with the risk information

described in the general investigational plan

or elsewhere in the current application, as

amended. For example, under this definition,

hepatic necrosis would be unexpected (by

virtue of greater severity) if the investigator

brochure only referred to elevated hepatic

enzymes or hepatitis. Similarly, cerebral

thromboembolism and cerebral vasculitis

would be unexpected (by virtue of greater

specificity) if the investigator brochure only

listed cerebral vascular accidents.

‘‘Unexpected,’’ as used in this definition,

refers to an adverse drug experience that has

not been previously observed (e.g., included

in the investigator brochure) rather than from

the perspective of such experience not being

anticipated from the pharmacological

properties of the pharmaceutical product.

3. IND Safety Reports. As proposed,

the final rule revises the time period for

submitting written IND safety reports,

under § 312.32(c)(1) and (d)(3), from 10

working days to 15 calendar days, and

revises the time period for submitting

telephone IND safety reports, under

§ 312.32(c)(2), from 3 working days to 7

calendar days. The final rule also

permits telephone safety reports to be

made by facsimile transmission under

§ 312.32(c)(2). The final rule, as

proposed with minor revisions for

clarity, also states, at § 312.32(c)(1)(i),

that FDA may require sponsors to

submit additional data.

In response to comments, FDA is

making minor revisions to its IND safety

reporting regulations to provide greater

consistency with the final ICH E2A

guideline. Currently, the requirement at

§ 312.32(b) states:

The sponsor shall promptly review all

information relevant to the safety of the drug

obtained or otherwise received by the

sponsor from any source, foreign or domestic,

including information derived from clinical

investigations, animal investigations,

commercial marketing experience, reports in

the scientific literature, and unpublished

scientific papers.

To clarify the phrase ‘‘any source,’’ FDA

is adding ‘‘epidemiological

investigations’’ and ‘‘foreign regulatory

authorities that have not already been

previously reported to the agency by the

sponsor’’ to the list of examples in

§ 312.32(b). This revision does not

impose a new burden because sponsors

are already required to review all

information relevant to the safety of the

drug obtained or otherwise received by

the sponsor from any source, foreign or

domestic. The amendment clarifies for

sponsors the type of safety information

that must be examined for

determination of whether information

should be submitted to the agency in

IND safety reports. This revision is

consistent with the final ICH E2A

guideline (60 FR 11284 at 11285 and

11286):

[Expedited reporting] applies to reports

from spontaneous sources and from any type

of clinical or epidemiological investigation,

independent of design or purpose.

The agency does not expect sponsors to

search adverse drug experience data

bases generated by regulatory

authorities for safety information or to

submit to FDA adverse drug experience

reports submitted to them by FDA.

FDA is also amending its IND safety

reporting regulations at § 312.32(c)(1)(i),

as noted above, by adding, with minor

revisions, language that is being moved

from the current definition of ‘‘serious

adverse experience’’ at § 312.32(a):

any finding from tests in laboratory

animals that suggests a significant risk for

human subjects including reports of

mutagenicity, teratogenicity, or

carcinogenicity.

This revision represents an

organizational change that does not

impose any new burden because

sponsors are currently required to report

such information to FDA. For clarity

and consistency, FDA is amending

§ 312.32(c)(1)(i) to state that reports

from animal studies and

epidemiological studies must be

submitted in a narrative format rather

than on FDA Form 3500A because FDA

Form 3500A has been designed for

reporting of adverse experience

information from an individual patient.

4. Postmarketing 15-day Alert and

Followup Reports. As proposed, the

final rule revises, at §§ 310.305(c),

314.80(c), and 600.80(c), the time period

for submitting postmarketing Alert

reports from 15 working days to 15

calendar days. For clarity, the final rule

is being amended, at § 310.305(c)(1)(i),
Federal Register / Vol. 62, No. 194 / Tuesday, October 7, 1997 / Rules and Regulations 52241

to state that the 15 calendar day

timeframe for reporting adverse drug

experiences on marketed prescription

drugs for human use without approved

new drug applications (NDA’s) begins

upon initial receipt of the information

by the person whose name appears on

the label. In addition, the final rule at

§§ 310.305(c)(2), 314.80(c)(1)(ii), and

600.80(c)(1)(ii), as proposed, advises

any person subject to the reporting

requirements under §§ 310.305(c),

314.80(c), and 600.80(c), who has been

unable to obtain additional information

for adverse drug experiences that are the

subject of postmarketing 15-day Alert

reports, to maintain records of their

unsuccessful attempts to seek additional

information. For clarity, the final rule is

being amended, at § 310.305(c)(2), to

state that 15-day Alert reports and

followups to them must be submitted

under separate cover.

The final rule specifies, like the

proposed rule, at §§ 310.305(c)(6),

314.80(b), and 600.80(b), that no one

subject to this rule is required to

resubmit to the agency reports of

adverse drug experiences that the

agency has forwarded to them. For

clarity, the final rule is being amended,

at §§ 310.305(c)(6), 314.80(b), and

600.80(b), to emphasize that followup

reports must be submitted for reports

received from the agency. The final rule

also requires, at §§ 310.305(a), 314.80(b),

and 600.80(b), any person subject to the

reporting requirements under

§§ 310.305(c), 314.80(c), and 600.80(c)

to develop written procedures for the

postmarketing surveillance, receipt,

evaluation, and reporting of adverse

drug experiences to FDA. In response to

comments, the final rule permits

persons subject to the reporting

requirements under §§ 310.305(c),

314.80(c), and 600.80(c) to submit

reports of serious adverse drug

experiences to a manufacturer,

applicant, or licensed manufacturer of a

final biological product instead of FDA

in 5 calendar days, instead of 3 calendar

days as proposed.

In this final rule, FDA is also

amending the postmarketing expedited

reporting regulations, at

§§ 314.80(c)(1)(i) and 600.80(c)(1)(i), by

replacing, in the first sentence, the

phrase ‘‘regardless of source’’ with the

phrase ‘‘whether foreign or domestic.’’

This amendment is consistent with

§§ 314.80(b) and 600.80(b) which

describe adverse drug experience

information that must be reviewed by

applicants and licensed manufacturers:

Each applicant (Any person having a

product license) * * * shall promptly review

all adverse drug experience information

(pertaining to its product) obtained or

otherwise received by the applicant (licensed

manufacturer) from any source, foreign or

domestic, including * * *.

FDA is making this revision to clarify

that 15-day Alert reports are to be

submitted for appropriate foreign as

well as domestic adverse drug

experiences.

5. Implementation Schedule. The

effective date for this final rule has been

extended to 180 days after its

publication in the Federal Register to

allow sufficient time for the agency to

comply with the provisions of the

Paperwork Reduction Act of 1995. Any

person subject to FDA’s mandatory

safety reporting requirements may

comply with the provisions of this final

rule prior to its effective date.

6. Guidances. In the Federal Register

of February 27, 1997 (62 FR 8961), FDA

published a notice of a guidance

document entitled ‘‘Good Guidance

Practices (GGP’s),’’ in which FDA

announced that notices of draft and

final guidances will be provided both in

the Federal Register and on the FDA

World Wide Web (WWW) home page

(http://www.fda.gov) (62 FR 8961 at

8965). In this final rule, FDA is

amending its postmarketing safety

reporting regulations at §§ 314.80(j) and

600.80(j) to remove reference to

guidelines prepared by the agency for

submission of reports of adverse drug

experiences and suggested followup

investigation of these reports. FDA is

also withdrawing its proposed

amendments of October 27, 1994,

regarding the availability of adverse

experience reporting guidelines under

§§ 310.305(g), 314.80(j), and 600.80(j).

FDA is making these amendments

because the guidance document of

February 27, 1997, describes processes

for timely notification of availability of

draft and final guidance documents and

it is no longer necessary for the agency

to include reference to these documents

in its postmarketing safety reporting

regulations.

At the present time, FDA is in the

process of revising guidances pertaining

to this final rule (CDER’s ‘‘Guideline for

Postmarketing Reporting of Adverse

Drug Experiences,’’ March 1992 and

CBER’s ‘‘Guideline for Adverse

Experience Reporting for Licensed

Biological Products,’’ October 1993) to

provide persons with the agency’s

current thinking on reporting of

postmarketing adverse drug

experiences. The agency will provide

notice of availability of any draft or final

guidance document pertaining to these

regulations in the Federal Register and

on the FDA WWW home page.

IV. Comments on the Proposed Rule

FDA received 57 comments on the

proposed rule from representatives of

pharmaceutical companies, health care

professional and pharmaceutical

associations, academic and government

institutions, and individuals. The

comments addressed all aspects of the

October 1994 proposal, including those

areas that are not being finalized in this

final rule. In general, the comments

endorsed FDA’s efforts in the proposal

to support global harmonization through

the adoption of certain ICH and CIOMS

recommendations. However, many

comments described areas where the

proposed regulations did not conform to

the international guidelines, and

recommended that the proposal be

revised to be more consistent. The

agency also received comments

recommending uniformity between its

pre- and postmarketing safety reporting

definitions. In response to these

comments, FDA, as described in section

III of this document, is amending its

regulations to implement additional

provisions recommended in the final

ICH E2A guideline and to provide

uniformity in its safety reporting

definitions.

A discussion of the comments

pertaining to this final rule and the

agency’s responses follows.

A. Definition of Disability

FDA proposed to define ‘‘disability,’’

in §§ 310.305(b), 314.80(a), and

600.80(a), as ‘‘a substantial disruption of

a person’s ability to carry out normal

life functions.’’

1. Eight comments requested

clarification of this definition. One

comment asked whether it included

missing work because of an adverse

experience, quitting a job, an inability to

get out of bed, or a decrease in earning

capacity. Another comment asked if it

included nausea, vomiting, and diarrhea

that would keep a person home from

work. One questioned whether the

proposed definition included events

such as migraine headaches, severe

influenza, or accidental trauma (e.g.,

sprained ankle). Another comment

contended that if the proposed

definition is intended to mean the

substantial disruption of normal life

functions, then such a condition would

require hospitalization or the in-house

use of life-support equipment.

FDA proposed to include the

definition of ‘‘disability’’ in the

regulations to enable reporters to

determine when a ‘‘serious’’ adverse

drug experience occurs. The extent of a

disability required for a serious adverse

drug experience is described in the
52242 Federal Register / Vol. 62, No. 194 / Tuesday, October 7, 1997 / Rules and Regulations

definition of ‘‘serious’’ by the phrase

‘‘* * * results in persistent or

significant disability/incapacity * * *.’’

Thus, only a persistent or significant or

incapacitating disability is intended.

The type of disability that would

constitute a serious adverse drug

experience is also described in the final

ICH E2A guideline, which states that a

serious adverse drug experience is based

on events that pose a threat to a

patient’s life or functioning and not on

events of relatively minor medical

significance (60 FR 11284 at 11285).

Thus, disability is not intended to

include experiences of relatively minor

medical significance such as headache,

nausea, vomiting, diarrhea, influenza,

and accidental trauma (e.g., sprained

ankle).

For clarity, FDA has revised the

proposed definition of ‘‘disability’’ by

substituting the words ‘‘to conduct’’ for

the words ‘‘to carry out.’’

To assure a consistent interpretation

of serious adverse drug experience in

premarketing and postmarketing safety

reporting, FDA has decided to revise the

‘‘definitions’’ section of the IND safety

reports regulation, at § 312.32(a), by

adding the definition of ‘‘disability’’ that

is used in the postmarketing safety

reporting regulations at §§ 310.305(b),

314.80(a), and 600.80(a).

B. Definition of Life-Threatening

FDA proposed to define ‘‘lifethreatening,’’ in §§ 310.305(b),

314.80(a), and 600.80(a), as follows:

[T]hat the patient was, in the view of the

initial reporter, at immediate risk of death

from the adverse experience as it occurred.

It does not include an adverse experience

that, had it occurred in a more serious form,

might have caused death. For example,

product-induced hepatitis that resolved

without evidence of hepatic failure would

not be considered life-threatening even

though hepatitis of a more severe nature can

be fatal. Similarly, an allergic reaction

resulting in angioedema of the face would

not be life-threatening, even though

angioedema of the larynx, allergic

bronchospasm, or anaphylaxis can be fatal.

2. Five comments opposed the use of

the phrase ‘‘in the view of the initial

reporter.’’ The comments stated that the

initial reporter could be a lay person

whose judgment of what constitutes an

‘‘immediate risk of death’’ may be

contrary to an evaluation by a medically

knowledgeable source. Several

comments suggested alternative

language for the definition to minimize

inaccurate reporting of events. One

comment requested deletion of the word

‘‘initial.’’ Another suggested changing

the phrase ‘‘initial reporter’’ to ‘‘a health

care professional directly associated

with the care of the patient,’’ while a

third recommended changing the word

‘‘reporter’’ to ‘‘health care provider who

reports the adverse experience.’’

FDA declines to amend the proposed

definition of ‘‘life-threatening’’ by

deleting or revising the phrase ‘‘in the

view of the initial reporter.’’ As

explained in the June 1993 notice (58

FR 31596 and 31604), FDA encourages

health care professionals and consumers

to report adverse drug experiences to

manufacturers. FDA Form 3500A

includes a section for identifying the

‘‘initial reporter’’ and for indicating the

reporter’s occupation and whether the

person is a health care professional.

Thus, the manufacturer and FDA will

know whether the adverse drug

experience report came from a lay

person or a health care professional and

can take that information into account

when evaluating the report.

Current IND safety reporting

regulations for telephone reports define

a ‘‘life-threatening’’ experience at

§ 312.32(c)(2), as:

* * * that the patient was, in the view of

the investigator, at immediate (emphasis

added) risk of death from the reaction as it

occurred, i.e., it does not include a reaction

that, had it occurred in a more serious form,

might have caused death. For example, druginduced hepatitis that resolved without

evidence of hepatic failure would not be

considered life-threatening even though

drug-induced hepatitis can be fatal.

FDA has decided, on its own initiative,

to remove the definition of ‘‘lifethreatening’’ from the telephone safety

reports section, at § 312.32(c)(2), and

add it to the general ‘‘definitions’’

section of § 312.32, at § 312.32(a). This

action will clarify that reporting of lifethreatening events apply to both written

and telephone IND safety reports. FDA

has also replaced ‘‘serious’’ with

‘‘severe’’ in the definition of ‘‘lifethreatening’’ to make it consistent with

the final ICH E2A guideline. FDA has

also decided, on its own initiative, to

add the words ‘‘or subject’’ after

‘‘patient’’ in this definition to clarify

that IND safety reports apply to healthy

subjects as well as patients. FDA has

also removed the last sentence in the

definition of ‘‘life-threatening’’ under

§ 312.32 (and the last two sentences in

the proposed postmarketing definition

of ‘‘life-threatening’’ under

§§ 310.305(b), 314.80(a), and 600.80(a)),

as noted in section III of this document,

to minimize confusion. The revised

definition of ‘‘life-threatening adverse

drug experience’’ in the IND safety

reporting regulations at § 312.32(a) reads

as follows:

Any adverse drug experience that places

the patient or subject, in the view of the

investigator, at immediate risk of death from

the reaction as it occurred, i.e., it does not

include a reaction that, had it occurred in a

more severe form, might have caused death.

C. Definition of Serious

FDA proposed to revise the definition

of ‘‘serious,’’ in §§ 310.305(b), 312.32(a),

314.80(a), and 600.80(a), to read as

follows:

Serious means an adverse drug experience

occurring at any dose that is fatal or lifethreatening, results in persistent or

significant disability/incapacity, requires or

prolongs inpatient hospitalization,

necessitates medical or surgical intervention

to preclude permanent impairment of a body

function or permanent damage to a body

structure, or is a congenital anomaly.

3. Twenty-five comments opposed all

or parts of the phrase ‘‘necessitates

medical or surgical intervention to

preclude permanent impairment of a

body function or permanent damage to

a body structure.’’ Nine comments

stated that this phrase makes the U.S.

definition of ‘‘serious’’ inconsistent with

harmonized safety reporting standards

such as the ICH E2A and E6 guidelines

and with the CIOMS II report. One

comment said that although the phrase

was included to provide a consistent

definition of what constitutes a serious

adverse event for all FDA-regulated

products, it causes inconsistency

between United States and international

reporting requirements. Another

comment said that the difference in

definitions between the United States

and the international community will

cause confusion and additional expense

for manufacturers who are complying

with the reporting requirements of

several countries. One comment stated

that if the definition is finalized as

proposed, preparation and submission

of a single postmarketing periodic report

worldwide will not be possible. Another

comment said that a definition as

important as ‘‘serious’’ should be

internationally consistent in order to be

easy to learn, quote, and recognize in

global clinical development and

medical safety. One comment noted that

it would be especially difficult to

implement the proposed criterion of

‘‘medical/surgical intervention’’ during

the course of an ongoing clinical study.

Ten comments recommended deletion

of the phrase. Eleven comments

requested clarification of the phrase

because it is too vague and

misinterpretation would result in

overreporting or underreporting of

adverse events. Another comment

suggested that the phrase be reworded

as an ‘‘unusual and potentially serious

experience that necessitates any medical

or surgical intervention.’’ One comment

recommended adopting the approach in

the final ICH E2A guideline of including

‘‘medical and surgical intervention’’
Federal Register / Vol. 62, No. 194 / Tuesday, October 7, 1997 / Rules and Regulations 52243

within the area of ‘‘other important

medical events.’’ The comment

indicated that the guideline leaves the

determination of whether or not such an

event is serious to medical and

scientific judgment.

As explained in the June 1993 notice

(58 FR 31596), FDA Forms 3500 and

3500A are designed to encourage and

facilitate the reporting of adverse events

and product problems for most FDAregulated human medical products by

the entire health care community,

including manufacturers, distributors,

user facilities, and health care

professionals. This includes reporting of

adverse events and product problems

with human drug products, biologics,

and medical devices, as well as other

FDA-regulated medical products.

FDA adopted several

recommendations from ICH and CIOMS

in developing the definitions used in

the forms and in the proposed

amendments to the safety reporting

regulations for human drug and

biological products. The agency believes

that certain standardized definitions,

procedures, and formats proposed by

ICH and CIOMS will result in more

effective and efficient safety reporting to

regulatory authorities worldwide. The

agency proposed to amend the

definition of ‘‘serious’’ to have a

consistent definition of what constitutes

a serious adverse drug experience for all

FDA-regulated products and to avoid

confusion about what events should be

reported to regulatory authorities

worldwide.

FDA agrees with the comments that

the differences between the definition of

serious, as proposed, and the definition

recommended in the final ICH E2A

guideline and in the CIOMS II report

may create confusion about what events

to report as serious. Therefore, the

agency has revised the definition of

‘‘serious’’ to be consistent with the final

ICH E2A guideline (60 FR 11284 at

11285) and FDA Forms 3500 and

3500A. The revised definition states:

Any adverse drug experience occurring at

any dose that results in any of the following

outcomes: Death, a life-threatening adverse

drug experience, inpatient hospitalization or

prolongation of existing hospitalization, a

persistent or significant disability/

incapacity, or a congenital anomaly/birth

defect. Important medical events that may

not result in death, be life-threatening, or

require hospitalization may be considered a

serious adverse drug experience when, based

upon appropriate medical judgment, they

may jeopardize the patient or subject and

may require medical or surgical intervention

to prevent one of the outcomes listed in this

definition. Examples of such medical events

include allergic bronchospasm requiring

intensive treatment in an emergency room or

at home, blood dyscrasias or convulsions that

do not result in inpatient hospitalization, or

the development of drug dependency or drug

abuse.

The term ‘‘serious’’ is defined

similarly in the final ICH E2A guideline

(60 FR 11284 at 11285) as:

A serious adverse event (experience) or

reaction is any untoward medical occurrence

that at any dose:

• Results in death,

• Is life-threatening,

* * *

• Requires inpatient hospitalization or

prolongation of existing hospitalization,

• Results in persistent or significant

disability/incapacity, or

• Is a congenital anomaly/birth defect.

Medical and scientific judgment should be

exercised in deciding whether expedited

reporting is appropriate in other situations,

such as important medical events that may

not be immediately life-threatening or result

in death or hospitalization but may

jeopardize the patient or may require

intervention to prevent one of the other

outcomes listed in the definition above.

These should also usually be considered

serious.

Examples of such events are intensive

treatment in an emergency room or at home

for allergic bronchospasm; blood dyscrasias

or convulsions that do not result in

hospitalization; or development of drug

dependency or drug abuse.

The revised definition of ‘‘serious’’ is

also consistent with section B.2 of FDA

Forms 3500 and 3500A, which directs

persons completing the forms to

indicate which of the following

outcomes is attributed to the adverse

event: ‘‘death, life-threatening,

hospitalization—initial or prolonged,

disability, congenital anomaly, required

intervention to prevent permanent

impairment/damage, or other.’’

In order to make the definition of

‘‘serious’’ in the premarketing safety

reporting regulations at § 312.32(a)

uniform with the revised definition of

‘‘serious’’ in the postmarketing safety

reporting regulations at §§ 310.305(b),

314.80(a), and 600.80(a), FDA is

removing the following sentence from

the current definition of ‘‘serious’’ at

§ 312.32(a), and adding it, with minor

revisions, to the IND written safety

reporting requirements under

§ 312.32(c)(1)(i):

With respect to results obtained from tests

in laboratory animals, a serious adverse drug

experience includes any experience

suggesting a significant risk for human

subjects, including any finding of

mutagenicity, teratogenicity, or

carcinogenicity.

4. One comment requested adding the

phrase ‘‘including overdose and

underdose’’ after the phrase ‘‘occurring

at any dose’’ in the definition of

‘‘serious’’ in order to eliminate

confusion. Otherwise, the comment

claimed, adverse outcomes associated

with underdoses may be interpreted as

a lack of therapeutic effect rather than

an adverse drug experience.

FDA declines to amend the definition

of ‘‘serious’’ to include the phrase

‘‘including overdose or underdose.’’ Use

of the phrase ‘‘occurring at any dose’’ in

the revised definition of ‘‘serious’’ will

ensure that serious adverse drug

experiences occurring at any dose,

including an overdose or an underdose,

must be reported.

5. Five comments asked for examples

of what is considered serious. One

comment asked whether intravenous

(IV) treatment for dehydration without

hospital admission or the use of IV

antibiotics, blood products, or dialysis

would be considered serious.

FDA advises that use of IV fluids,

antibiotics, or blood products, or

dialysis may or may not be serious,

depending on why they are being used.

A decision using medical judgment

should be made based on the

circumstances surrounding each case.

As stated in the revised definition of

‘‘serious’’, other examples include

allergic bronchospasm requiring

intensive treatment in an emergency

room or at home, blood dyscrasias or

convulsions that do not result in

inpatient hospitalization, and the

development of drug dependency or

drug abuse.

6. Five comments requested

clarification of the following sentence in

the preamble to the proposed rule under

the discussion of the definition of

‘‘serious’’: ‘‘FDA notes that a serious

adverse experience would not include

the discontinuation of therapy, changes

in dosage, or routine treatment with a

prescription medication’’ (59 FR 54046

at 54048). One comment stated that the

sentence should also be included in the

codified definition of ‘‘serious’’ because

the qualifiers are extremely important in

limiting the range of events not

considered serious. Three comments

asked for clarification of the phrase

‘‘routine treatment with a prescription

medication.’’ One of these comments

noted that treatment with any new

medication could potentially be

considered a medical intervention and

therefore could be classified as serious.

Another comment requested

clarification of the phrase ‘‘would not

include discontinuation of therapy’’

because it implies that discontinuation

of therapy in response to a clinically

significant rise in serum

aminotransferases or serum creatinine

would not be considered intervention

and therefore would not be serious.

FDA declines to revise the definition

of ‘‘serious’’ to include examples of

events not considered serious. FDA
52244 Federal Register / Vol. 62, No. 194 / Tuesday, October 7, 1997 / Rules and Regulations

clarifies that discontinuation of therapy,

changes in dosage, and routine

treatment with a prescription

medication are not in themselves

serious events but may occur as the

result of a serious event.

7. Several comments discussed the

use of the words ‘‘persistent’’ and

‘‘permanent’’ in the definition of

‘‘serious’’. One comment requested

rewording the phrase ‘‘persistent or

significant disability’’ to read

‘‘permanent or persistent disability.’’

Another comment suggested that the

term ‘‘permanent disability’’ in the

current definition of ‘‘serious’’ should

be retained because replacing

‘‘permanent’’ with ‘‘persistent’’ does not

further define disability. The comment

noted that a condition like influenza

might be significantly incapacitating but

may not qualify as a serious event.

Three comments recommended

changing the word ‘‘permanent’’ to

‘‘persistent’’ in the phrase ‘‘preclude

permanent impairment of a body

function or permanent damage to a body

system.’’ One comment requested that

the phrase ‘‘persistent or significant

disability’’ be used instead of

‘‘permanent or significant disability’’ in

the definition of ‘‘serious’’ in proposed

§ 312.32(a) in order to be consistent

with proposed §§ 310.305(b), 314.80(a),

and 600.80(a).

As explained in the preamble to the

October 1994 proposal (59 FR 54046 at

54047), FDA is revising the phrase ‘‘is

permanently disabling’’ to ‘‘results in a

persistent or significant disability/

incapacity’’ in order to clarify that a

disability need not be permanent to be

considered a serious adverse drug

experience. Thus, FDA declines to

substitute the phrase ‘‘permanent or

persistent disability’’ for ‘‘persistent or

significant disability’’ or retain

‘‘permanent disability.’’ In addition,

FDA has corrected the typographical

error in proposed § 312.32(a) by revising

‘‘permanent or significant disability’’ to

read ‘‘persistent or significant

disability.’’

8. One comment requested the

addition of the word ‘‘immediately’’

before ‘‘life-threatening’’ in the

definition of ‘‘serious’’. The comment

stated that although ‘‘immediate’’ is

stated in the definition of ‘‘lifethreatening’’, it is not indicated on FDA

Form 3500 or 3500A. As a result,

reporters may interpret ‘‘lifethreatening’’ to mean ‘‘potentially’’ lifethreatening rather than ‘‘immediately’’

life-threatening.

FDA declines to revise the definition

of ‘‘serious’’ to add the word

‘‘immediately’’ before ‘‘life-threatening’’

because the phrase ‘‘at immediate risk of

death’’ is part of the definition of ‘‘lifethreatening adverse drug experience.’’

Although the word ‘‘immediately’’ does

not appear before the word ‘‘lifethreatening’’ on FDA Forms 3500 and

3500A, the MedWatch ‘‘FDA Desk

Guide for Adverse Event and Product

Problem Reporting’’ explains that a lifethreatening adverse event would be

immediate.

D. IND Safety Reports—Written

FDA proposed to revise the

requirements for submitting written IND

safety reports, under § 312.32(c)(1) and

(d)(3), by altering the time period for

submitting such reports from 10

working days to 15 calendar days. In

addition, FDA proposed to permit

sponsors to submit written IND safety

reports to the agency by using FDA

Form 3500A or in a narrative format. If

a sponsor chose to use FDA Form

3500A, additional narrative data might

be required if the agency determined

that insufficient data were submitted on

the form.

9. Three comments expressed support

for the 15 calendar days timeframe. One

comment commended FDA for requiring

the same timeframe for both pre- and

postmarketing expedited reporting. Two

other comments requested that the

timeframe be increased to 20 calendar

days, while another comment

recommended any period longer than 15

calendar days. The comments stated

that 15 calendar days would not provide

enough time for the submission of

reports or for contacting non-U.S.

physicians. One comment noted that a

longer timeframe would permit better

review and reporting of serious adverse

experiences.

As explained in the October 1994

proposal (59 FR 54046 at 54051), FDA

believes that the extended timeframe is

sufficient for sponsors to gather

appropriate data to help initially

interpret the reports before submitting

them to FDA. This timeframe is also

consistent with the 15 calendar day

period in the final ICH E2A guideline

(60 FR 11284 at 11286).

10. Although one comment expressed

support for use of FDA Form 3500A for

written IND safety reports because it

would provide consistency with the

form for postmarketing reports, another

comment requested that the form not be

required for these reports because of

limited space for describing narrative

information.

FDA notes that it is not ‘‘requiring’’

use of FDA Form 3500A for written IND

safety reports. Reporters may use the

form or, alternatively, may submit these

reports in a narrative format. In

addition, as explained in the June 1993

notice announcing the availability of the

form, reporters may use additional

blank sheets of paper, referenced to the

section of the form being described, to

complete any narrative sections of the

form.

In the June 1993 notice (58 FR 31596

at 31598), FDA also stated that

companies may use the CIOMS I form

for reporting foreign events after

obtaining FDA approval. FDA has

decided, based on comments to its

postmarketing safety reporting

regulations (see section IV.F of this

document), to amend § 312.32(c)(1) to

permit use of the CIOMS I form for

reporting foreign events without prior

approval. FDA has decided to take this

action to expedite reporting of foreign

events and harmonize its pre- and

postmarketing safety reporting

regulations.

11. One comment requested

clarification about what sponsors must

include in a written IND safety report.

The comment also requested guidance

on how often a report should be

submitted and whether one is required

every time a new case is reported.

Under § 312.32(b), as amended in this

final rule, FDA requires that the sponsor

must promptly review all information

relevant to the safety of the drug

obtained or otherwise received by the

sponsor from any source, foreign or

domestic, including information derived

from any clinical or epidemiological

investigations, animal investigations,

commercial marketing experience,

reports in the scientific literature, and

unpublished scientific papers, as well as

reports from foreign regulatory

authorities that have not already been

previously reported to the agency by the

sponsor. This requirement qualifies for

sponsors the type of safety information

that must be examined for

determination of whether the

information should be included in IND

safety reports.

As noted earlier, FDA is amending its

IND safety reports regulations, at

§ 312.32, by moving, for organizational

purposes, certain information from the

current definition of ‘‘serious adverse

experience,’’ at § 312.32(a), to the

written IND safety reports section, at

§ 312.32(c)(1)(i). Under § 312.32(c)(1)(i),

as revised in this final rule, sponsors

must submit written IND safety reports

to FDA and all participating

investigators within 15 calendar days

after the sponsor’s receipt of

information on any adverse experience

associated with the use of the drug that

is both serious and unexpected; or any

finding from tests in laboratory animals

that suggests a significant risk for

human subjects including reports of
Federal Register / Vol. 62, No. 194 / Tuesday, October 7, 1997 / Rules and Regulations 52245

mutagenicity, teratogenicity, or

carcinogenicity.

FDA advises sponsors, as described in

greater detail in the final ICH E2A

guideline (60 FR 11284 at 11285 and

11286), to submit in written IND safety

reports as much information as possible

on a case. In some instances,

information for final description and

evaluation of a case report may not be

available within 15 calendar days.

Nevertheless, initial reports should be

submitted within this timeframe when

the following minimum criteria are met:

An identifiable patient; a suspected

medicinal product; an identifiable

reporter; and an adverse event or

outcome that can be identified as

serious and unexpected, and for which,

in clinical investigation cases, there is a

reasonable suspected causal

relationship between the investigational

product and the adverse event (i.e., the

causal relationship cannot be ruled out).

For reportable events that occur during

a ‘‘blinded’’ clinical investigation,

sponsors should only break the blind for

the subject in question. Sponsors should

consult with the FDA review division

responsible for their IND in situations in

which the sponsor believes that

breaking the blind would compromise

their study (e.g., when a fatal or other

serious outcome is the primary efficacy

endpoint in a clinical investigation).

Reportable events attributed to a

specific dosage form, formulation, or

route of administration should be crossreferenced to other IND’s for the drug.

Reportable events associated with a

particular population or for a specific

indication should also be crossreferenced to other IND’s for the drug.

FDA expects sponsors to submit

written IND safety reports every time

the sponsor receives or otherwise

obtains information about a serious and

unexpected adverse experience

associated with the use of the drug until

the current investigator brochure or, if

the investigator brochure is not

required, until the risk information

described in the general investigational

plan or elsewhere in the current

application is amended. This is

consistent with the final ICH E2A

guideline (60 FR 11284 at 11285): ‘‘Until

source documents are amended,

expedited reporting is required for

additional occurrences of the reaction.’’

12. One comment asked when a

written safety report would be due if the

15th day occurs on a weekend or

holiday.

FDA advises that if the 15th calendar

day occurs on a weekend or U.S.

Federal holiday, the written safety

report would be due the 1st working day

after the weekend or U.S. Federal

holiday.

E. IND Safety Reports—Telephone

FDA proposed to revise the

requirements for submitting IND safety

reports by telephone, under

§ 312.32(c)(2), by altering the time

period for submitting such reports from

3 working days to 7 calendar days. FDA

also proposed to allow telephone safety

reports to be made by facsimile

transmission.

13. Two comments expressed support

for the 7 calendar day timeframe. Other

comments requested longer timeframes

because 7 days does not provide a

significant difference from the current

time period, and because additional

time is needed for contacting non-U.S.

physicians. One comment asked for a

timeframe of 10 calendar days, and

another requested any period longer

than 7 calendar days.

FDA declines to lengthen the

timeframe for IND safety reports by

telephone or facsimile transmission.

FDA believes it is important that

unexpected fatal or life-threatening

experiences associated with the use of

the drug be reported to the agency as

expeditiously as possible. A 7 calendar

day timeframe is reasonable for these

types of reports. This timeframe is also

consistent with recommendations in the

final ICH E2A guideline (60 FR 11284 at

11286).

14. Three comments supported FDA’s

proposal to accept telephone safety

reports by ‘‘facsimile transmission.’’ The

comments also requested that FDA

permit transmission of these reports by

other electronic mechanisms such as

Internet or electronic mail systems.

In the Federal Register of March 20,

1997 (62 FR 13430), FDA published a

final rule that permits the agency to

accept electronic records, electronic

signatures, and handwritten signatures

executed to electronic records as

generally equivalent to paper records

and handwritten signatures executed on

paper. FDA stated in this final rule that

it will announce in the Federal Register

when it is prepared to accept certain

submissions in electronic format only.

At the present time, FDA is not

prepared to accept electronic

submission of IND safety reports, but is

developing a system to accept such

submissions in the future.

15. One comment requested that FDA

restore the phrase ‘‘in the clinical

studies conducted under the IND’’ to the

language in § 312.32(c)(2) for telephone

safety reports of any unexpected fatal or

life-threatening experience associated

with the use of the drug. The phrase did

not appear in the October 27, 1994,

proposed revisions to this section.

It is FDA’s intention not to restrict

telephone safety reports of any

unexpected fatal or life-threatening

experience associated with the use of

the drug to clinical studies conducted

under the IND. As stated under

§ 312.32(b), as revised in this final rule,

the sponsor shall promptly review all

information relevant to the safety of the

drug obtained or otherwise received by

the sponsor from any source, foreign or

domestic, including information derived

from any clinical or epidemiological

investigations, animal investigations,

commercial marketing experience,

reports in the scientific literature, and

unpublished scientific papers, as well as

reports from foreign regulatory

authorities that have not already been

previously reported to the agency by the

sponsor. Thus, the sponsor is

responsible for notifying FDA by

telephone or facsimile transmission, as

soon as possible, but in no event later

than 7 calendar days, of any unexpected

fatal or life-threatening experience

associated with the use of the drug from

any source. This requirement is

consistent with the final ICH E2A

guideline (60 FR 11284 at 11286):

Information obtained by a sponsor or

manufacturer on serious, unexpected reports

from any source should be submitted on an

expedited basis to appropriate regulatory

authorities if the minimum criteria for

expedited reporting can be met.

F. Postmarketing Alert and Followup

Reports

FDA proposed to amend

§§ 310.305(c), 314.80(c), and 600.80(c)

by reorganizing, renumbering, and

retitling the paragraphs in these sections

to distinguish between postmarketing

15-day Alert reports and followups to

these reports. FDA also proposed to

distinguish between the reporting

intervals for postmarketing 15-day Alert

reports and the intervals proposed for

postmarketing periodic reports. In

addition, FDA proposed to amend

§§ 310.305(c)(1) through (c)(4),

314.80(c)(1)(i) through (c)(1)(iv), and

600.80(c)(1)(i) through (c)(1)(iv), to alter

the time period for submitting

postmarketing 15-day Alert reports and

followup reports from 15 working days

to 15 calendar days.

16. Twelve comments stated that the

15 calendar day timeframe is overly

burdensome. One comment noted that

the change from 15 working days to 15

calendar days would result in

approximately one-third (6 days) less

time for preparation of reports for

submission to FDA. Another comment

indicated that, although the proposed
52246 Federal Register / Vol. 62, No. 194 / Tuesday, October 7, 1997 / Rules and Regulations

timeframe is in accord with the final

ICH E2A guideline, it would cause

significant disruption in reporting

schedules and would probably result in

incomplete reports. Another comment

stated that the revised timeframe would

not provide international companies

with sufficient time to receive and

translate foreign reports. One comment

said that the proposed timeframe

incorrectly assumes that reporters are

universally accessible anywhere in the

world. Six comments offered

suggestions for alternative timeframes.

Three comments recommended 20

calendar days, one recommended 21

calendar days, and another

recommended 22 calendar days. Two of

the comments encouraged retention of

the 15 working day timeframe currently

required by FDA.

FDA declines to revise its proposed

15 calendar day timeframe for

postmarketing Alert reports. The agency

proposed to revise the reporting period

from 15 working days to 15 calendar

days to provide consistency in pre- and

postmarketing safety reporting

timeframes for products and to decrease

misunderstandings with reporting

requirements by stating all timeframes

in terms of calendar days. This

timeframe is consistent with the 15

calendar day reporting timeframe in the

final ICH E2A guideline (60 FR 11284 at

11286) and consistent with the change

in timeframe set forth in this final rule

at § 312.32(c)(1) and (d)(3) for IND safety

reporting of serious and unexpected

experiences. This timeframe is sufficient

for persons subject to the postmarketing

safety reporting requirements to gather

appropriate data and initially interpret

reports before submitting them to the

agency.

In this final rule, FDA is amending its

postmarketing expedited safety

reporting regulations, at

§ 310.305(c)(1)(i), by adding the

following phrase to the end of the first

sentence: ‘‘by the person whose name

appears on the label.’’ FDA is making

this revision to clarify when the 15

calendar day timeframe begins for

marketed prescription drugs for human

use without approved new drug

applications. This change is consistent

with current language under

§§ 314.80(c)(1)(i) and 600.80(c)(1)(i) for

marketed prescription drugs for human

use with approved NDA’s and for

licensed biological products. Under

§ 314.80(c)(1)(i), 15-day Alert reports

must be submitted no later than 15

calendar days of initial receipt of

information by the applicant. Under

§ 600.80(c)(1)(i), such reports must be

submitted within the same timeframe

based on initial receipt of information

by the licensed manufacturer.

17. Two comments requested that

they be permitted to use the CIOMS I

form for reporting foreign events as an

alternative to FDA Form 3500A without

obtaining prior FDA approval. In

addition, the comments preferred using

the CIOMS I form instead of FDA Form

3500A for all adverse drug experience

reporting worldwide.

In the June 1993 notice, the agency

stated that reporters may use the CIOMS

I form for reporting foreign events with

prior FDA approval. FDA has

considered the comments and has

decided to revise §§ 310.305, 314.80,

and 600.80 to permit the use of the

CIOMS I form for reports of foreign

events without first obtaining prior FDA

approval. FDA is taking this action to

expedite the reporting of foreign events.

FDA will continue to require use of

FDA Form 3500A for reports of

domestic events. FDA Form 3500A is

more comprehensive than the CIOMS I

form and includes elements

recommended by the final ICH E2A

guideline that are not part of the CIOMS

I form (60 FR 11284 at 11287). For

example, the following items are

included in FDA Form 3500A and

requested in the ICH E2A guideline but

are not included in the CIOMS I form:

Body weight, the terms ‘‘congenital

anomaly’’ and ‘‘other’’ (identifiers of

adverse event outcomes), the lot number

and dosage strength of suspected

medicinal product(s), details on the

event reporter, and the regulatory code

number (e.g., IND/NDA number).

18. One comment requested that FDA

accept postmarketing 15-day Alert and

followup reports through electronic

transmission.

As explained above, FDA has

published a final rule to permit the

agency to accept electronic records,

electronic signatures, and handwritten

signatures executed to electronic

records as generally equivalent to paper

records and handwritten signatures

executed on paper (62 FR 13430). At the

present time, FDA is not prepared to

accept electronic submission of 15-day

Alert reports, but is developing a system

to accept such submissions in the

future.

G. Written Procedures for Monitoring

Adverse Drug Experiences

FDA proposed to amend

§§ 310.305(a), 314.80(b), and 600.80(b)

to require that any person subject to the

reporting requirements under

§§ 310.305(c), 314.80(c), and 600.80(c)

develop written procedures for the

surveillance, receipt, evaluation, and

reporting of adverse drug experiences to

FDA.

19. One comment opposed this

amendment. The comment stated that

these written procedures are customary

and usual in the industry and, if made

part of a regulation, could be potentially

burdensome to manufacturers and

would permit FDA to dictate internal

procedures.

FDA declines to withdraw this

proposed amendment. As explained in

the preamble to the October 1994

proposal (59 FR 54046 at 54053), this

requirement would improve

postmarketing surveillance by

applicants and manufacturers and

would enhance an applicant’s and a

manufacturer’s ability to evaluate and

report adverse drug experiences to the

agency. In addition, because such

written procedures are usual and

customary, FDA believes that this

provision would not impose a new

burden on applicants and

manufacturers.

20. One comment stated that it is

inappropriate to require packers and

distributors to develop written

procedures for the surveillance, receipt,

evaluation, and reporting of adverse

drug experiences to FDA if they elect to

submit these reports to the

manufacturer.

Under §§ 310.305(c)(1)(i),

314.80(c)(1)(iv), and 600.80(c)(1)(iv),

packers and distributors are subject to

the reporting requirements if their name

appears on the label of a marketed

prescription drug product or licensed

biological product. A packer or

distributor who elects to submit adverse

drug experience reports to an applicant,

manufacturer, or licensed manufacturer

of a final biological product under

§§ 310.305(c)(4), 314.80(c)(1)(iv), and

600.80(c)(1)(iv) must include

information about making such an

election in their written procedures, as

well as procedures for recordkeeping

required to be maintained under these

regulations. For the reasons explained

in the October 1994 proposal (59 FR

54046 at 54053), it is appropriate to

require that these packers and

distributors develop written procedures

to ensure that they comply with these

regulations.

21. One comment requested that FDA

specify the minimum requirements for a

company’s written procedures for

reporting adverse drug experiences.

FDA declines to specify minimum

requirements for written reporting

procedures. As explained in the October

1994 proposal (59 FR 54046 at 54053),

written procedures for handling adverse

drug experiences are customary and

usual in the pharmaceutical industry. In
Federal Register / Vol. 62, No. 194 / Tuesday, October 7, 1997 / Rules and Regulations 52247

addition, such procedures have been

required for many years by FDA’s

current good manufacturing practice

(CGMP) regulations for finished

pharmaceuticals (21 CFR 211.198).

H. Submission of Postmarketing 15-day

Alert Reports by Persons Other Than

Applicants, Manufacturers, and

Licensed Manufacturers of a Final

Biological Product

Current postmarketing safety

reporting regulations, at § 310.305(c)(5),

permit packers and distributors to

submit reports of serious adverse drug

experiences to the manufacturer instead

of FDA. Under § 314.80(c)(1)(iii),

manufacturers, packers, and distributors

may submit these reports to the

applicant. Under § 600.80(c)(1)(iii),

packers, distributors, and manufacturers

other than licensed manufacturers of the

final biological product may submit

these reports to the licensed

manufacturer of the final product.

Currently, these reports must be

submitted within 3 working days of

their receipt. FDA proposed to revise

this timeframe to 3 calendar days. The

manufacturer, applicant, and licensed

manufacturer of the final biological

product would then comply with the

requirements described in this section

by submitting the report to FDA as soon

as possible, but in no case later than 15

calendar days of initial receipt of the

information.

22. Five comments opposed changing

3 working days to 3 calendar days

because the new timeframe is overly

burdensome, especially if the period

includes holidays or weekends. One

comment said that manufacturers,

packers, distributors, and shared and

joint manufacturers would probably

submit these reports directly to FDA in

order to utilize the longer timeframe.

This would result in duplicative

reporting to the agency. The comments

suggested alternative timeframes. Three

comments recommended 5 calendar

days, one recommended 7 calendar

days, and another recommended that

the current requirement of 3 working

days be maintained.

FDA agrees with the comments and

has revised the final rule at

§§ 310.305(c)(4), 314.80(c)(1)(iv), and

600.80(c)(1)(iv) to permit manufacturers,

packers, and distributors, as well as

manufacturers, packers, distributors,

shared manufacturers, joint

manufacturers, and any other

participant involved in divided

manufacturing of a biological product,

to submit reports of serious adverse

drug experiences to the manufacturer,

applicant, or licensed manufacturer of

the final biological product in 5

calendar days.

23. One comment requested that the

regulations state that manufacturers

should not submit to FDA reports it

receives from a reporter, if the reporter

has submitted the report to FDA.

FDA declines to revise its regulations

to exempt manufacturers from

submitting safety reports to FDA that it

receives from a voluntary reporter who

has submitted the report to FDA,

regardless of whether the reporter is a

physician, pharmacist, or other health

care professional, or a consumer. The

agency requires manufacturers to submit

such reports to FDA to ensure that the

agency receives all safety reports.

However, as now stated at

§§ 310.305(c)(6), 314.80(b), and

600.80(b), no one subject to the

postmarketing safety reporting

regulations at §§ 310.305(c), 314.80(c),

and 600.80(c) is required to resubmit to

the agency FDA Form 3500A reports

that the agency has forwarded to them.

I. General Comments

24. One comment asked whether the

Federal Register notices announcing the

availability of FDA Forms 3500 and

3500A had been withdrawn, revised, or

replaced by the October 1994 proposal.

The comment indicated that the

effective date for FDA Form 3500A was

put on hold pending revision of the

regulations for safety reporting.

The June 1993 notice (58 FR 31596),

announced the availability of FDA

Forms 3500 and 3500A. The use of FDA

Form 3500 was effective immediately,

while the use of FDA Form 3500A was

scheduled to be effective on November

30, 1993. Manufacturers, medical device

distributors, and user facilities were

encouraged to begin using the form

immediately. In the Federal Register of

December 3, 1993 (58 FR 64001), FDA

extended the effective date for use of

FDA Form 3500A until FDA issues a

final rule amending the regulations to

require the use of the form. This final

rule makes the requirement for use of

FDA Form 3500A effective on April 6,

1998.

25. Four comments requested that

FDA publish guidelines to explain the

proposed regulations. Two of the

comments asked whether a draft

guideline could be published with an

opportunity for public comment before

publication of the final rule.

In the Federal Register of March 1,

1995 (60 FR 11284), FDA published the

final ICH E2A guideline ‘‘Clinical Safety

Data Management: Definitions and

Standards for Expedited Reporting.’’

Concerning the opportunity for

comment on guidances, on July 9, 1993

(58 FR 37408), FDA published the draft

ICH E2A guideline for public comment.

As described under section III of this

document, FDA is in the process of

revising guidances pertaining to this

final rule and will provide opportunity

for public comment and notice of

availability of any draft or final

guidance documents in the Federal

Register and on FDA’s WWW home

page, under the GGP’s (62 FR 8961).

26. One comment asked whether

information on the United Kingdom

Medicines Control Agency’s Medical

Dictionary for Drug Regulatory Affairs

would be incorporated into the final

rule.

This terminology was not discussed

in the proposed rule and will not be

incorporated into this final rule. At the

September 1994 CIOMS meeting, it was

agreed that this terminology would be

the basis for the development of a new

international medical terminology to

support classification of terms relating

to all aspects of drug regulation. In July

1997, ICH developed a final consensus

guideline on this topic (ICH M1). At this

time, FDA is considering the ICH M1

document.

V. Environmental Impact

The agency has determined under 21

CFR 25.30(h) 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. Analysis of Impacts

The agency has considered the

potential economic impact of this final

rule under Executive Order 12866, the

Regulatory Flexibility Act (5 U.S.C.

601–612), as amended by Subtitle D of

the Small Business Regulatory Fairness

Act of 1996 (Pub. L. 104–721), and the

Unfunded Mandates Reform Act of 1995

(Pub. L. 104–4). 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.
52248 Federal Register / Vol. 62, No. 194 / Tuesday, October 7, 1997 / Rules and Regulations

The Regulatory Flexibility Act

requires agencies to analyze regulatory

options that would minimize any

significant impact of a rule on small

entities. The agency certifies that the

final rule will not have a significant

economic impact on a substantial

number of small entities. According to

the Small Business Administration,

manufacturers of medicinals and

botanicals or pharmaceutical

preparations with 750 or less

employees, and manufacturers of

diagnostic substances or biological

products with 500 or less employees are

considered a small business. As

discussed in section VII of this

document, modifications and additions

to the recordkeeping requirements will

not result in a change in industry’s

current recordkeeping burden hours.

Therefore, under the Regulatory

Flexibility Act, no further analysis is

needed.

The final rule will also not impose

annual expenditures of $100 million or

more on either State, local, and tribal

governments in aggregate, or on the

private sector. Therefore, a written

statement and economic analysis is not

required as prescribed under section

202(a) of the Unfunded Mandates

Reform Act of 1995.

VII. Paperwork Reduction Act of 1995

This final rule contains information

collection provisions that are subject to

review by the Office of Management and

Budget (OMB) under the Paperwork

Reduction Act of 1995 (44 U.S.C. 3501–

3520). The title, description, and

respondent description of the

information collection provisions are

shown below.

Title: Expedited Safety Reporting

Requirements for Human Drug and

Biological Products; Final Rule.

Description: FDA is amending its

current expedited safety reporting

requirements to replace current Form

FDA–1639 with new FDA Form 3500A;

to revise certain definitions, reporting

periods and formats; to require

applicants, manufacturers, packers, and

distributors, as well as licensed

manufacturers and other manufacturers

of biological products to develop

written procedures for postmarketing

safety monitoring and reporting of

adverse drug experiences to FDA; and to

make other revisions to provide

uniformity to the expedited pre- and

postmarketing safety reporting

regulations. These changes will simplify

and facilitate expedited safety reporting

and enhance agencywide consistency in

the collection of postmarketing safety

data.

Respondent Description: Businesses

and other for-profit organizations, State

or local governments, Federal agencies,

and nonprofit institutions.

FDA believes that this final rule will

not result in any increase in paperwork

burden as compared to current

expedited safety reporting requirements.

The new requirement under

§§ 310.305(a), 314.80(b), and 600.80(b),

that persons subject to the

postmarketing safety reporting

requirements develop written

procedures for the surveillance, receipt,

evaluation, and reporting to FDA of

adverse drug experiences, does not

impose a new burden because it codifies

a practice that is already customary and

usual in the pharmaceutical industry for

handling adverse drug experiences.

The new recordkeeping requirements

under §§ 310.305(c)(2), 314.80(c)(1)(ii),

and 600.80(c)(1)(ii), that persons subject

to the postmarketing safety reporting

requirements maintain records of

unsuccessful attempts to obtain

additional followup information on 15-

day Alert reports, do not result in a

change in the burden. Current

regulations provide for submission of a

followup report describing steps taken

to seek additional information and the

reasons why it could not be obtained;

FDA estimates that the effort needed to

file this existing information will be, at

worst, no more than the effort that

would have been required to submit it

to FDA.

The new language in § 312.32(b)

explicitly requiring that sponsors

review: (1) Information derived from

any epidemiological investigations, or

(2) reports from foreign regulatory

authorities that have not already been

previously reported to the agency by the

sponsor does not impose a new burden

because this amendment is only a

clarification. Sponsors are already

required to review all information

relevant to the safety of the drug

obtained or otherwise received by the

sponsor from any source, foreign or

domestic.

Although the October 1994 proposal

provided a 90-day comment period

under the Paperwork Reduction Act of

1980, FDA is providing an additional

opportunity for public comment under

the Paperwork Reduction Act of 1995,

which was enacted after the expiration

of the comment period and applies to

this final rule. Therefore, FDA now

invites comments on: (1) Whether the

proposed collection of information is

necessary for the proper performance of

FDA’s functions, including whether the

information will have practical utility;

(2) the accuracy of FDA’s estimate of the

burden of the proposed collection of

information, including the validity of

the methodology and assumptions used;

(3) ways to enhance the quality, utility,

and clarity of the information to be

collected; and (4) ways to minimize the

burden of the collection of information

on respondents, including through the

use of automated collection techniques,

when appropriate, and other forms of

information technology. Individuals and

organizations may submit comments on

the information collection provisions of

this final rule by December 8, 1997.

Comments should be directed to the

Dockets Management Branch (address

above).

At the close of the 60-day comment

period, FDA will review the comments

received, revise the information

collection provisions as necessary, and

submit these provisions to OMB for

review and approval. FDA will publish

a notice in the Federal Register when

the information collection provisions

are submitted to OMB, and an

opportunity for public comment to OMB

will be provided at that time. Prior to

the effective date of this final rule, FDA

will publish a notice in the Federal

Register of OMB’s decision to approve,

modify, or disapprove the information

collection provisions. An agency may

not conduct or sponsor, and a person is

not required to respond to, a collection

of information unless it displays a

currently valid OMB control number.

VIII. References

The following references have been

placed on display at the Dockets

Management Branch (address above)

and may be seen by interested persons

between 9 a.m. and 4 p.m., Monday

through Friday.

1. International Reporting of Periodic DrugSafety Update Summaries, Final Report of

CIOMS Working Group II, 1992.

2. International Reporting of Adverse Drug

Reactions, Final Report of CIOMS Working

Group I, 1990.

List of Subjects

21 CFR Part 20

Confidential business information,

Courts, Freedom of information,

Government employees.

21 CFR Part 310

Administrative practice and

procedure, Drugs, Labeling, Medical

devices, Reporting and recordkeeping

requirements.

21 CFR Part 312

Drugs, Exports, Imports,

Investigations, Labeling, Medical

research, Reporting and recordkeeping

requirements, Safety.
Federal Register / Vol. 62, No. 194 / Tuesday, October 7, 1997 / Rules and Regulations 52249

21 CFR Part 314

Administrative practice and

procedure, Confidential business

information, Drugs, Reporting and

recordkeeping requirements.

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 parts 20, 310, 312,

314, and 600 are amended as follows:

PART 20—PUBLIC INFORMATION

1. The authority citation for 21 CFR

part 20 continues to read as follows:

Authority: Secs. 201–903 of the Federal

Food, Drug, and Cosmetic Act (21 U.S.C.

321–393); secs. 301, 302, 303, 307, 310, 311,

351, 352, 354–360F, 361, 362, 1701–1706,

2101 of the Public Health Service Act (42

U.S.C. 241, 242, 242a, 242l, 242n, 243, 262,

263, 263b–263n, 264, 265, 300u–300u–5,

300aa–1); 5 U.S.C. 552; 18 U.S.C. 1905; 19

U.S.C. 2531–2582; 21 U.S.C. 1401–1403.

§ 20.112 [Amended]

2. Section 20.112 Voluntary drug

experience reports submitted by

physicians and hospitals is amended in

paragraph (a) by removing the words

‘‘Form FDA–1639’’ and adding in their

place ‘‘FDA Form 3500’’.

PART 310—NEW DRUGS

3. The authority citation for 21 CFR

part 310 continues to read as follows:

Authority: Secs. 201, 301, 501, 502, 503,

505, 506, 507, 512–516, 520, 601(a), 701, 704,

705, 721 of the Federal Food, Drug, and

Cosmetic Act (21 U.S.C. 321, 331, 351, 352,

353, 355, 356, 357, 360b–360f, 360j, 361(a),

371, 374, 375, 379e); secs. 215, 301, 302(a),

351, 354–360F of the Public Health Service

Act (42 U.S.C. 216, 241, 242(a), 262, 263b–

263n).

4. Section 310.305 is amended by

adding a new sentence at the end of

paragraph (a); by revising paragraphs

(b), (c), (d)(1), (d)(3)(ii), and (d)(4); by

removing in paragraph (d)(2), the

introductory text of paragraph (d)(3),

and paragraph (d)(3)(i) the words ‘‘Form

FDA–1639’’ or ‘‘FDA–1639’’ and adding

in their place ‘‘FDA Form 3500A’’ to

read as follows:

§ 310.305 Records and reports concerning

adverse drug experiences on marketed

prescription drugs for human use without

approved new drug applications.

(a) * * * Any person subject to the

reporting requirements of paragraph (c)

of this section shall also develop written

procedures for the surveillance, receipt,

evaluation, and reporting of

postmarketing adverse drug experiences

to FDA.

(b) Definitions. The following

definitions of terms apply to this

section:

Adverse drug experience. Any adverse

event associated with the use of a drug

in humans, whether or not considered

drug related, including the following:

An adverse event occurring in the

course of the use of a drug product in

professional practice; an adverse event

occurring from drug overdose whether

accidental or intentional; an adverse

event occurring from drug abuse; an

adverse event occurring from drug

withdrawal; and any failure of expected

pharmacological action.

Disability. A substantial disruption of

a person’s ability to conduct normal life

functions.

Life-threatening adverse drug

experience. Any adverse drug

experience that places the patient, in the

view of the initial reporter, at immediate

risk of death from the adverse drug

experience as it occurred, i.e., it does

not include an adverse drug experience

that, had it occurred in a more severe

form, might have caused death.

Serious adverse drug experience. Any

adverse drug experience occurring at

any dose that results in any of the

following outcomes: Death, a lifethreatening adverse drug experience,

inpatient hospitalization or

prolongation of existing hospitalization,

a persistent or significant disability/

incapacity, or a congenital anomaly/

birth defect. Important medical events

that may not result in death, be lifethreatening, or require hospitalization

may be considered a serious adverse

drug experience when, based upon

appropriate medical judgment, they may

jeopardize the patient or subject and

may require medical or surgical

intervention to prevent one of the

outcomes listed in this definition.

Examples of such medical events

include allergic bronchospasm requiring

intensive treatment in an emergency

room or at home, blood dyscrasias or

convulsions that do not result in

inpatient hospitalization, or the

development of drug dependency or

drug abuse.

Unexpected adverse drug experience.

Any adverse drug experience that is not

listed in the current labeling for the

drug product. This includes events that

may be symptomatically and

pathophysiologically related to an event

listed in the labeling, but differ from the

event because of greater severity or

specificity. For example, under this

definition, hepatic necrosis would be

unexpected (by virtue of greater

severity) if the labeling only referred to

elevated hepatic enzymes or hepatitis.

Similarly, cerebral thromboembolism

and cerebral vasculitis would be

unexpected (by virtue of greater

specificity) if the labeling only listed

cerebral vascular accidents.

‘‘Unexpected,’’ as used in this

definition, refers to an adverse drug

experience that has not been previously

observed (i.e., included in the labeling)

rather than from the perspective of such

experience not being anticipated from

the pharmacological properties of the

pharmaceutical product.

(c) Reporting requirements. Each

person identified in paragraph (c)(1)(i)

of this section shall report to FDA

adverse drug experience information as

described in this section and shall

submit one copy of each report to the

Division of Pharmacovigilance and

Epidemiology (HFD–730), Center for

Drug Evaluation and Research, Food

and Drug Administration, 5600 Fishers

Lane, Rockville, MD 20857.

(1) Postmarketing 15-day ‘‘Alert

reports’’. (i) Any person whose name

appears on the label of a marketed

prescription drug product as its

manufacturer, packer, or distributor

shall report to FDA each adverse drug

experience received or otherwise

obtained that is both serious and

unexpected as soon as possible, but in

no case later than 15 calendar days of

initial receipt of the information by the

person whose name appears on the

label. Each report shall be accompanied

by a copy of the current labeling for the

drug product.

(ii) A person identified in paragraph

(c)(1)(i) of this section is not required to

submit a 15-day ‘‘Alert report’’ for an

adverse drug experience obtained from

a postmarketing study (whether or not

conducted under an investigational new

drug application) unless the applicant

concludes that there is a reasonable

possibility that the drug caused the

adverse experience.

(2) Postmarketing 15-day ‘‘Alert

reports’’—followup. Each person

identified in paragraph (c)(1)(i) of this

section shall promptly investigate all

serious, unexpected adverse drug

experiences that are the subject of these

postmarketing 15-day Alert reports and

shall submit followup reports within 15

calendar days of receipt of new

information or as requested by FDA. If

additional information is not obtainable,

records should be maintained of the

unsuccessful steps taken to seek

additional information. Postmarketing

15-day Alert reports and followups to

them shall be submitted under separate

cover.
52250 Federal Register / Vol. 62, No. 194 / Tuesday, October 7, 1997 / Rules and Regulations

(3) Submission of reports. To avoid

unnecessary duplication in the

submission of, and followup to, reports

required in this section, a packer’s or

distributor’s obligations may be met by

submission of all reports of serious

adverse drug experiences to the

manufacturer of the drug product. If a

packer or distributor elects to submit

these adverse drug experience reports to

the manufacturer rather than to FDA, it

shall submit each report to the

manufacturer within 5 calendar days of

its receipt by the packer or distributor,

and the manufacturer shall then comply

with the requirements of this section

even if its name does not appear on the

label of the drug product. Under this

circumstance, the packer or distributor

shall maintain a record of this action

which shall include:

(i) A copy of each adverse drug

experience report;

(ii) The date the report was received

by the packer or distributor;

(iii) The date the report was submitted

to the manufacturer; and

(iv) The name and address of the

manufacturer.

(4) Each report submitted to FDA

under this section shall bear prominent

identification as to its contents, i.e., ‘‘15-

day Alert report,’’ or ‘‘15-day Alert

report-followup.’’

(5) A person identified in paragraph

(c)(1)(i) of this section is not required to

resubmit to FDA adverse drug

experience reports forwarded to that

person by FDA; however, the person

must submit all followup information on

such reports to FDA.

(d) * * * (1) Except as provided in

paragraph (d)(3) of this section, each

person identified in paragraph (c)(1)(i)

of this section shall submit each report

of a serious and unexpected adverse

drug experience on an FDA Form 3500A

(foreign events may be submitted either

on an FDA Form 3500A or, if preferred,

on a CIOMS I form).

* * * * *

(3) * * *

(ii) The format is agreed to in advance

by MedWatch: The FDA Medical

Products Reporting Program.

(4) Ten copies or fewer of FDA Form

3500A and/or a copy of the instructions

for completing the form may be

obtained from the Division of

Pharmacovigilance and Epidemiology

(HFD–730), Center for Drug Evaluation

and Research, Food and Drug

Administration, 5600 Fishers Lane,

Rockville, MD 20857. More than 10

copies of the form may be obtained by

writing to the Consolidated Forms and

Publications Distribution Center,

Washington Commerce Center, 3222

Hubbard Rd., Landover, MD 20785.

* * * * *

PART 312—INVESTIGATIONAL NEW

DRUG APPLICATION

5. The authority citation for 21 CFR

part 312 continues to read as follows:

Authority: Secs. 201, 301, 501, 502, 503,

505, 506, 507, 701 of the Federal Food, Drug,

and Cosmetic Act (21 U.S.C. 321, 331, 351,

352, 353, 355, 356, 357, 371); sec. 351 of the

Public Health Service Act (42 U.S.C. 262).

6. Section 312.32 is amended by

revising paragraphs (a), (b), (c)(1)(i),

(c)(2), and (d)(3); by adding in the

second sentence of paragraph (c)(3) the

words ‘‘new drug review’’ before the

phrase ‘‘division in the Center for Drug

Evaluation and Research’’ and the

words ‘‘the director of the product

review division in’’ before the phrase

‘‘the Center for Biologics Evaluation and

Research’’; and by removing in

paragraph (e) the word ‘‘section’’ and

replacing it with the word ‘‘part’’, to

read as follows:

§ 312.32 IND safety reports.

(a) Definitions. The following

definitions of terms apply to this

section:

Associated with the use of the drug.

There is a reasonable possibility that the

experience may have been caused by the

drug.

Disability. A substantial disruption of

a person’s ability to conduct normal life

functions.

Life-threatening adverse drug

experience. Any adverse drug

experience that places the patient or

subject, in the view of the investigator,

at immediate risk of death from the

reaction as it occurred, i.e., it does not

include a reaction that, had it occurred

in a more severe form, might have

caused death.

Serious adverse drug experience: Any

adverse drug experience occurring at

any dose that results in any of the

following outcomes: Death, a lifethreatening adverse drug experience,

inpatient hospitalization or

prolongation of existing hospitalization,

a persistent or significant disability/

incapacity, or a congenital anomaly/

birth defect. Important medical events

that may not result in death, be lifethreatening, or require hospitalization

may be considered a serious adverse

drug experience when, based upon

appropriate medical judgment, they may

jeopardize the patient or subject and

may require medical or surgical

intervention to prevent one of the

outcomes listed in this definition.

Examples of such medical events

include allergic bronchospasm requiring

intensive treatment in an emergency

room or at home, blood dyscrasias or

convulsions that do not result in

inpatient hospitalization, or the

development of drug dependency or

drug abuse.

Unexpected adverse drug experience:

Any adverse drug experience, the

specificity or severity of which is not

consistent with the current investigator

brochure; or, if an investigator brochure

is not required or available, the

specificity or severity of which is not

consistent with the risk information

described in the general investigational

plan or elsewhere in the current

application, as amended. For example,

under this definition, hepatic necrosis

would be unexpected (by virtue of

greater severity) if the investigator

brochure only referred to elevated

hepatic enzymes or hepatitis. Similarly,

cerebral thromboembolism and cerebral

vasculitis would be unexpected (by

virtue of greater specificity) if the

investigator brochure only listed

cerebral vascular accidents.

‘‘Unexpected,’’ as used in this

definition, refers to an adverse drug

experience that has not been previously

observed (e.g., included in the

investigator brochure) rather than from

the perspective of such experience not

being anticipated from the

pharmacological properties of the

pharmaceutical product.

(b) Review of safety information. The

sponsor shall promptly review all

information relevant to the safety of the

drug obtained or otherwise received by

the sponsor from any source, foreign or

domestic, including information derived

from any clinical or epidemiological

investigations, animal investigations,

commercial marketing experience,

reports in the scientific literature, and

unpublished scientific papers, as well as

reports from foreign regulatory

authorities that have not already been

previously reported to the agency by the

sponsor.

(c) IND safety reports. (1) Written

reports—(i) The sponsor shall notify

FDA and all participating investigators

in a written IND safety report of:

(A) Any adverse experience

associated with the use of the drug that

is both serious and unexpected; or

(B) Any finding from tests in

laboratory animals that suggests a

significant risk for human subjects

including reports of mutagenicity,

teratogenicity, or carcinogenicity. Each

notification shall be made as soon as

possible and in no event later than 15

calendar days after the sponsor’s initial

receipt of the information. Each written

notification may be submitted on FDA
Federal Register / Vol. 62, No. 194 / Tuesday, October 7, 1997 / Rules and Regulations 52251

Form 3500A or in a narrative format

(foreign events may be submitted either

on an FDA Form 3500A or, if preferred,

on a CIOMS I form; reports from animal

or epidemiological studies shall be

submitted in a narrative format) and

shall bear prominent identification of its

contents, i.e., ‘‘IND Safety Report.’’ Each

written notification to FDA shall be

transmitted to the FDA new drug review

division in the Center for Drug

Evaluation and Research or the product

review division in the Center for

Biologics Evaluation and Research that

has responsibility for review of the IND.

If FDA determines that additional data

are needed, the agency may require

further data to be submitted.

* * * * *

(2) Telephone and facsimile

transmission safety reports. The sponsor

shall also notify FDA by telephone or by

facsimile transmission of any

unexpected fatal or life-threatening

experience associated with the use of

the drug as soon as possible but in no

event later than 7 calendar days after the

sponsor’s initial receipt of the

information. Each telephone call or

facsimile transmission to FDA shall be

transmitted to the FDA new drug review

division in the Center for Drug

Evaluation and Research or the product

review division in the Center for

Biologics Evaluation and Research that

has responsibility for review of the IND.

* * * * *

(d) * * *

(3) If the results of a sponsor’s

investigation show that an adverse drug

experience not initially determined to

be reportable under paragraph (c) of this

section is so reportable, the sponsor

shall report such experience in a written

safety report as soon as possible, but in

no event later than 15 calendar days

after the determination is made.

* * * * *

PART 314—APPLICATIONS FOR FDA

APPROVAL TO MARKET A NEW DRUG

OR AN ANTIBIOTIC DRUG

7. The authority citation for 21 CFR

part 314 continues to read as follows:

Authority: Secs. 201, 301, 501, 502, 503,

505, 506, 507, 701, 704, 721 of the Federal

Food, Drug, and Cosmetic Act (21 U.S.C. 321,

331, 351, 352, 353, 355, 356, 357, 371, 374,

379e).

8. Section 314.80 is amended by

revising paragraphs (a), (c)(1), (f)(1),

(f)(3)(ii), and (f)(4) and the introductory

text of paragraph (c); by adding two new

sentences at the end of paragraph (b); by

removing in paragraph (d)(2) the words

‘‘Epidemiology and Surveillance’’ and

adding in their place the words

‘‘Pharmacovigilance and

Epidemiology’’; by removing in

paragraphs (c)(2)(ii)(b), (d)(2), (f)(2), and

(f)(3) and in the heading for paragraph

(f) the words ‘‘Form FDA–1639’’ or

‘‘FDA–1639’’ and adding in their place

the words ‘‘FDA Form 3500A’’; and by

removing paragraph (j) and

redesignating paragraphs (k) and (l) as

paragraphs (j) and (k), respectively, to

read as follows:

§ 314.80 Postmarketing reporting of

adverse drug experiences.

(a) Definitions. The following

definitions of terms apply to this

section:

Adverse drug experience. Any adverse

event associated with the use of a drug

in humans, whether or not considered

drug related, including the following:

An adverse event occurring in the

course of the use of a drug product in

professional practice; an adverse event

occurring from drug overdose whether

accidental or intentional; an adverse

event occurring from drug abuse; an

adverse event occurring from drug

withdrawal; and any failure of expected

pharmacological action.

Disability. A substantial disruption of

a person’s ability to conduct normal life

functions.

Life-threatening adverse drug

experience. Any adverse drug

experience that places the patient, in the

view of the initial reporter, at immediate

risk of death from the adverse drug

experience as it occurred, i.e., it does

not include an adverse drug experience

that, had it occurred in a more severe

form, might have caused death.

Serious adverse drug experience. Any

adverse drug experience occurring at

any dose that results in any of the

following outcomes: Death, a lifethreatening adverse drug experience,

inpatient hospitalization or

prolongation of existing hospitalization,

a persistent or significant disability/

incapacity, or a congenital anomaly/

birth defect. Important medical events

that may not result in death, be lifethreatening, or require hospitalization

may be considered a serious adverse

drug experience when, based upon

appropriate medical judgment, they may

jeopardize the patient or subject and

may require medical or surgical

intervention to prevent one of the

outcomes listed in this definition.

Examples of such medical events

include allergic bronchospasm requiring

intensive treatment in an emergency

room or at home, blood dyscrasias or

convulsions that do not result in

inpatient hospitalization, or the

development of drug dependency or

drug abuse.

Unexpected adverse drug experience.

Any adverse drug experience that is not

listed in the current labeling for the

drug product. This includes events that

may be symptomatically and

pathophysiologically related to an event

listed in the labeling, but differ from the

event because of greater severity or

specificity. For example, under this

definition, hepatic necrosis would be

unexpected (by virtue of greater

severity) if the labeling only referred to

elevated hepatic enzymes or hepatitis.

Similarly, cerebral thromboembolism

and cerebral vasculitis would be

unexpected (by virtue of greater

specificity) if the labeling only listed

cerebral vascular accidents.

‘‘Unexpected,’’ as used in this

definition, refers to an adverse drug

experience that has not been previously

observed (i.e., included in the labeling)

rather than from the perspective of such

experience not being anticipated from

the pharmacological properties of the

pharmaceutical product.

(b) * * * Applicants are not required

to resubmit to FDA adverse drug

experience reports forwarded to the

applicant by FDA; however, applicants

must submit all followup information

on such reports to FDA. Any person

subject to the reporting requirements

under paragraph (c) of this section shall

also develop written procedures for the

surveillance, receipt, evaluation, and

reporting of postmarketing adverse drug

experiences to FDA.

(c) Reporting requirements. The

applicant shall report to FDA adverse

drug experience information, as

described in this section. The applicant

shall submit two copies of each report

described in this section to the Central

Document Room, 12229 Wilkins Ave.,

Rockville, MD 20852. FDA may waive

the requirement for the second copy in

appropriate instances.

(1)(i) Postmarketing 15-day ‘‘Alert

reports’’. The applicant shall report each

adverse drug experience that is both

serious and unexpected, whether

foreign or domestic, as soon as possible

but in no case later than 15 calendar

days of initial receipt of the information

by the applicant.

(ii) Postmarketing 15-day ‘‘Alert

reports’’—followup. The applicant shall

promptly investigate all adverse drug

experiences that are the subject of these

postmarketing 15-day Alert reports and

shall submit followup reports within 15

calendar days of receipt of new

information or as requested by FDA. If

additional information is not obtainable,

records should be maintained of the

unsuccessful steps taken to seek

additional information. Postmarketing

15-day Alert reports and followups to
52252 Federal Register / Vol. 62, No. 194 / Tuesday, October 7, 1997 / Rules and Regulations

them shall be submitted under separate

cover.

(iii) Submission of reports. The

requirements of paragraphs (c)(1)(i) and

(c)(1)(ii) of this section, concerning the

submission of postmarketing 15-day

Alert reports, shall also apply to any

person other than the applicant

(nonapplicant) whose name appears on

the label of an approved drug product

as a manufacturer, packer, or

distributor. To avoid unnecessary

duplication in the submission to FDA of

reports required by paragraphs (c)(1)(i)

and (c)(1)(ii) of this section, obligations

of a nonapplicant may be met by

submission of all reports of serious

adverse drug experiences to the

applicant. If a nonapplicant elects to

submit adverse drug experience reports

to the applicant rather than to FDA, the

nonapplicant shall submit each report to

the applicant within 5 calendar days of

receipt of the report by the

nonapplicant, and the applicant shall

then comply with the requirements of

this section. Under this circumstance,

the nonapplicant shall maintain a

record of this action which shall

include:

(A) A copy of each adverse drug

experience report;

(B) The date the report was received

by the nonapplicant;

(C) The date the report was submitted

to the applicant; and

(D) The name and address of the

applicant.

(iv) Report identification. Each report

submitted under this paragraph shall

bear prominent identification as to its

contents, i.e., ‘‘15-day Alert report,’’ or

‘‘15-day Alert report-followup.’’

* * * * *

(f) * * * (1) Except as provided in

paragraph (f)(3) of this section, the

applicant shall complete FDA Form

3500A for each report of an adverse

drug experience (foreign events may be

submitted either on an FDA Form

3500A or, if preferred, on a CIOMS I

form).

* * * * *

(3) * * * (ii) the format is agreed to

in advance by MedWatch: The FDA

Medical Products Reporting Program.

(4) Ten copies or fewer of FDA Form

3500A and/or a copy of the instructions

for completing the form may be

obtained from the Division of

Pharmacovigilance and Epidemiology

(HFD–730), Center for Drug Evaluation

and Research, Food and Drug

Administration, 5600 Fishers Lane,

Rockville, MD 20857. More than 10

copies of the form may be obtained by

writing to the Consolidated Forms and

Publications Distribution Center,

Washington Commerce Center, 3222

Hubbard Rd., Landover, MD 20785.

* * * * *

PART 600—BIOLOGICAL PRODUCTS:

GENERAL

9. The authority citation for 21 CFR

part 600 continues 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).

10. Section 600.80 is amended by

revising paragraphs (a), (c)(1), (f)(1), and

the first sentence of paragraph (g); by

adding two new sentences at the end of

paragraph (b); and by removing

paragraph (j) and redesignating

paragraphs (k), (l), and (m) as

paragraphs (j), (k), and (l), respectively,

to read as follows:

§ 600.80 Postmarketing reporting of

adverse experiences.

(a) Definitions. The following

definitions of terms apply to this

section:

Adverse experience. Any adverse

event associated with the use of a

biological product in humans, whether

or not considered product related,

including the following: An adverse

event occurring in the course of the use

of a biological product in professional

practice; an adverse event occurring

from overdose of the product whether

accidental or intentional; an adverse

event occurring from abuse of the

product; an adverse event occurring

from withdrawal of the product; and

any failure of expected pharmacological

action.

Blood Component. As defined in

§ 606.3(c) of this chapter.

Disability. A substantial disruption of

a person’s ability to conduct normal life

functions.

Life-threatening adverse experience.

Any adverse experience that places the

patient, in the view of the initial

reporter, at immediate risk of death from

the adverse experience as it occurred,

i.e., it does not include an adverse

experience that, had it occurred in a

more severe form, might have caused

death.

Serious adverse experience. Any

adverse experience occurring at any

dose that results in any of the following

outcomes: Death, a life-threatening

adverse experience, inpatient

hospitalization or prolongation of

existing hospitalization, a persistent or

significant disability/incapacity, or a

congenital anomaly/birth defect.

Important medical events that may not

result in death, be life-threatening, or

require hospitalization may be

considered a serious adverse experience

when, based upon appropriate medical

judgment, they may jeopardize the

patient or subject and may require

medical or surgical intervention to

prevent one of the outcomes listed in

this definition. Examples of such

medical events include allergic

bronchospasm requiring intensive

treatment in an emergency room or at

home, blood dyscrasias or convulsions

that do not result in inpatient

hospitalization, or the development of

drug dependency or drug abuse.

Unexpected adverse experience: Any

adverse experience that is not listed in

the current labeling for the biological

product. This includes events that may

be symptomatically and

pathophysiologically related to an event

listed in the labeling, but differ from the

event because of greater severity or

specificity. For example, under this

definition, hepatic necrosis would be

unexpected (by virtue of greater

severity) if the labeling only referred to

elevated hepatic enzymes or hepatitis.

Similarly, cerebral thromboembolism

and cerebral vasculitis would be

unexpected (by virtue of greater

specificity) if the labeling only listed

cerebral vascular accidents.

‘‘Unexpected,’’ as used in this

definition, refers to an adverse

experience that has not been previously

observed (i.e., included in the labeling)

rather than from the perspective of such

experience not being anticipated from

the pharmacological properties of the

pharmaceutical product.

(b) * * * Licensed manufacturers are

not required to resubmit to FDA adverse

product experience reports forwarded to

the licensed manufacturer by FDA;

licensed manufacturers, however, must

submit all followup information on such

reports to FDA. Any person subject to

the reporting requirements under

paragraph (c) of this section shall also

develop written procedures for the

surveillance, receipt, evaluation, and

reporting of postmarketing adverse

experiences to FDA.

(c) * * *

(1)(i) Postmarketing 15-day ‘‘Alert

reports’’. The licensed manufacturer

shall report each adverse experience

that is both serious and unexpected,

whether foreign or domestic, as soon as

possible but in no case later than 15

calendar days of initial receipt of the

information by the licensed

manufacturer.

(ii) Postmarketing 15-day ‘‘Alert

reports’’—followup. The licensed

manufacturer shall promptly investigate
Federal Register / Vol. 62, No. 194 / Tuesday, October 7, 1997 / Rules and Regulations 52253

all adverse experiences that are the

subject of these postmarketing 15-day

Alert reports and shall submit followup

reports within 15 calendar days of

receipt of new information or as

requested by FDA. If additional

information is not obtainable, records

should be maintained of the

unsuccessful steps taken to seek

additional information. Postmarketing

15-day Alert reports and followups to

them shall be submitted under separate

cover.

(iii) Submission of reports. The

requirements of paragraphs (c)(1)(i) and

(c)(1)(ii) of this section, concerning the

submission of postmarketing 15-day

Alert reports, shall also apply to any

person whose name appears on the label

of a licensed biological product as a

manufacturer, packer, distributor,

shared manufacturer, joint

manufacturer, or any other participant

involved in divided manufacturing. To

avoid unnecessary duplication in the

submission to FDA of reports required

by paragraphs (c)(1)(i) and (c)(1)(ii) of

this section, obligations of persons other

than the licensed manufacturer of the

final biological product may be met by

submission of all reports of serious

adverse experiences to the licensed

manufacturer of the final product. If a

person elects to submit adverse

experience reports to the licensed

manufacturer of the final product rather

than to FDA, the person shall submit

each report to the licensed manufacturer

of the final product within 5 calendar

days of receipt of the report by the

person, and the licensed manufacturer

of the final product shall then comply

with the requirements of this section.

Under this circumstance, a person who

elects to submit reports to the licensed

manufacturer of the final product shall

maintain a record of this action which

shall include:

(A) A copy of all adverse biological

product experience reports submitted to

the licensed manufacturer of the final

product;

(B) The date the report was received

by the person;

(C) The date the report was submitted

to the licensed manufacturer of the final

product; and

(D) The name and address of the

licensed manufacturer of the final

product.

(iv) Report identification. Each report

submitted under this paragraph shall

bear prominent identification as to its

contents, i.e., ‘‘15-day Alert report,’’ or

‘‘15-day Alert report-followup.’’

* * * * *

(f) Reporting forms. (1) Except as

provided in paragraph (f)(3) of this

section, the licensed manufacturer shall

complete the reporting form designated

by FDA for each report of an adverse

experience (FDA Form 3500A, or, for

vaccines, a VAERS form; foreign events

including those associated with the use

of vaccines, may be submitted either on

an FDA Form 3500A or, if preferred, on

a CIOMS I form).

* * * * *

(g) Multiple reports. A licensed

manufacturer should not include in

reports under this section any adverse

experience that occurred in clinical

trials if they were previously submitted

as part of the license application. * * *

* * * * *

Dated: September 25, 1997.

William K. Hubbard,

Associate Commissioner for Policy

Coordination.

[FR Doc. 97–26255 Filed 10–6–97; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Parts 1309, 1310 and 1313

[DEA Number 154F]

RIN 1117–AA42

Implementation of the Comprehensive

Methamphetamine Control Act of 1996;

Possession of List I Chemicals

Definitions, Record Retention, and

Temporary Exemption From Chemical

Registration for Distributors of

Combination Ephedrine Products

AGENCY: Drug Enforcement

Administration (DEA), Justice.

ACTION: Final rule.

SUMMARY: DEA is finalizing the Interim

Rule, which included a request for

comment, published in the Federal

Register on February 10, 1997, (62 FR

5914). The Interim Rule amended the

regulations to incorporate certain

amendments to the Controlled

Substances Act (CSA) made by the

Comprehensive Methamphetamine

Control Act of 1996 (MCA) and to

provide temporary exemption from

registration for persons who distribute

combination ephedrine products.

Comments were received regarding

industry interpretation of certain

requirements of both the CSA and the

MCA. This notice responds to those

comments and clarifies the

requirements of the CSA and MCA with

respect to the distribution of

combination ephedrine products.

EFFECTIVE DATE: October 7, 1997.

FOR FURTHER INFORMATION CONTACT: G.

Thomas Gitchel, Chief, Liaison and

Policy Section, Office of Diversion

Control, Drug Enforcement

Administration, Washington, D.C.

20537, Telephone (202) 307–7297.

SUPPLEMENTARY INFORMATION: On

February 10, 1997, DEA published an

interim rule, with request for comment,

in the Federal Register (62 FR 5914) to

implement certain regulatory changes

mandated by the MCA and to provide

temporary exemption from registration

pending promulgation of final

regulations to implement the MCA.

Five comments were received

regarding the interim rule. Three

separate issues were raised in the

comments:

(1) Two comments expressed support

for the temporary exemptions and urged

that the exemption from registration for

retail distributors as described in the

MCA be made permanent. DEA agrees

and will make the exemption

permanent.

(2) Three comments asserted that

DEA’s interpretation of the MCA is

incorrect and that the registration

requirement does not apply to

wholesale distributors that engage in

only sub-threshold transactions of

combination ephedrine products.

Specifically, the commentors assert

that while Section 302(a)(1) of the CSA

(21 U.S.C. 822(a)(1)) requires that any

person who distributes a List I chemical

must register, that requirement is

tempered by Section 303(h) of the CSA

(21 U.S.C. 823(h)), which provides, in

part, that registration shall not be

required for the distribution of a drug

product that is exempted under section

102(39)(A)(iv). Section 102(39) of the

CSA (21 U.S.C. 802(39)) defines the

term ‘‘regulated transaction’’. The

definition provides in paragraph (A)(iv)

that a transaction in a listed chemical

contained in a drug product that may be

marketed or distributed under the Food,

Drug, and Cosmetic Act (FDC Act) is not

a regulated transaction, unless the drug

contains ephedrine, pseudoephedrine,

or phenylpropanolamine, and the

quantity of ephedrine,

pseudoephedrine, or

phenylpropanolamine equals or exceeds

the threshold established for the

chemical. These provisions are echoed

in DEA’s regulations; Title 21, Code of

Federal Regulations (CFR), Section

1309.21(a) requires registration for the

distribution of a List I chemical, other

than a List I chemical contained in a

drug product that is exempted under 21

CFR section 1310.01(f)(1)(iv). The

commentors assert the definition of

regulated transaction provides that a